Quinuclidine derivatives binding to mucarinic m3 receptors

ABSTRACT

Compounds of formula I  
                 
 
in salt or zwitterionic form wherein, wherein R 1 , R 2 , R 3 , and R 4  have the meanings as indicated in the specification, are useful for treating conditions that are mediated by the muscarinic M3 receptor. Pharmaceutical compositions that contain the compounds and a process for preparing the compounds are also described.

This invention relates to organic compounds, their preparation and useas pharmaceuticals.

In one aspect the invention provides compounds of formula I

in salt or zwitterionic form whereinR¹ and R³ are each independently a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—;R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyl optionallysubstituted by hydroxy;R⁴ is C₃-C₁₀-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NRS—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹, —O—CO—NHR¹², —O—CO—R¹³ or —CO—O—R¹⁴, orR⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;R⁵ is hydrogen or C₁-C₈-alkyl;R⁶ is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in eachcase optionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or R⁶ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;R⁷ is a C₃-C₁₅-carbocyclic group;R⁸ is a C₃-C₁₅-carbocyclic group;R⁹ is hydrogen or C₁-C₈-alkyl;R¹⁰ is hydrogen, C₁-C₈-alkyl optionally substituted by cyano, amino,nitro, carboxy, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group, or by a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;R¹¹ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkyl-C₁-C₈-alkoxy orC₁-C₈-alkyl-O—R¹⁵;

-   R¹² is a C₃-C₁₅-carbocyclic group;-   R¹³ is C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group;-   R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group, C₁-C₈-alkenyl, or    C₁-C₈-alkyl optionally substituted by a C₃-C₁₅-carbocyclic group;    and    R¹⁵ is a C₃-C₁₅-carbocyclic group.

Terms used in the specification have the following meanings:

“Optionally substituted” means the group referred to can be substitutedat one or more positions, e.g. 1, 2 or 3 positions, by any one or anycombination of the radicals described.

“C₁-C₈-alkyl” as used herein denotes straight chain or branched alkylhaving 1 to 8 carbon atoms. Preferably, C₁-C₈-alkyl is C₁-C₄-alkyl.

“C₁-C₈-alkylene” as used herein denotes straight chain or branchedalkylene that contains 1 to 8 carbon atoms. Preferably, C₁-C₈-alkyleneis C₁-C₄-alkylene.

“C₂-C₈-alkenyl” as used herein denotes straight chain or branchedhydrocarbon chains that contain two to eight carbon atoms and one ormore carbon-carbon double bonds. Preferably “C₂-C₈-alkenyl” is“C₂-C₄-alkenyl”.

“C₂-C₁₀-alkynyl” as used herein denotes straight chain or branchedhydrocarbon chains that contain two to ten carbon atoms and one or morecarbon-carbon triple bonds. Preferably “C₂-C₁₀-alkynyl” is“C₃-C₈-alkynyl”.

“C₃-C₁₅-carbocyclic group” as used herein denotes a carbocyclic grouphaving 3 to 15 ring carbon atoms, for example a monocyclic group, eithercycloaliphatic, such as a C₃-C₈-cycloalkyl, or aromatic such as phenyl,which can be substituted by one or more, usually one or two, C₁-C₄-alkylgroups, or a bicyclic group such as bicyclooctyl, bicyclononyl includingindanyl and indenyl, and bicyclodecyl including naphthyl, again any ofwhich can be substituted by one or more, usually one or two, C₁-C₄-alkylgroups. Preferably the C₃-C₁₅-carbocyclic group is a C₃-C₁₀-carbocyclicgroup, for example cyclopropyl, cyclopentyl, cyclohexyl, cyclohepcyl,phenyl, indanyl or naphthyl. The C₃-C₁₅-carbocyclic group can besubstituted or unsubstituted. Preferred substituents include halo (e.g.fluoro, chloro or bromo), cyano, hydroxy, amino, nitro, carboxy,C₁-C₈-alkyl (e.g. methyl or ethyl), halo-C₁-C₈-alkyl, C₁-C₈-alkoxy,C₁-C₈-alkylcarbonyl, C₁-C₈-alkylsulfonyl, —SO₂NH₂, a C₃-C₁₅-carbocyclicgroup and a 5- to 12-membered heterocyclic group having at least onering heteroatom selected from nitrogen, oxygen and sulphur.

“C₃-C₈-cycloalkyl” as used herein denotes cycloalkyl having 3 to 8carbon atoms. Preferably “C₃-C₈-cycloalkyl” is “C₃-C₆-cycloalkyl”.

“C₁-C₈-haloalkyl” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined substituted by one or more halogen atoms, preferably one, two orthree halogen atoms. Preferably “C₁-C₈-haloalkyl” is “C₁-C₄-haloalkyl”.

“C₁-C₈-alkylcarbonyl” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined linked to a carbonyl group. Preferably “C₁-C₈-alkylcarbonyl” is“C₁-C₄-alkylcarbonyl”.

“C₁-C₈-alkylthio” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined linked to —S—. Preferably “C₁-C₈-alkylthio” is“C₁-C₄-alkylthio”.

“C₁-C₈-alkylsulfonyl” as used herein denotes C₁-C₈-alkyl as hereinbeforedefined linked to —SO₂—. Preferably “C₁-C₈-alkylsulfonyl” is“C₁-C₄-alkylsulfonyl”.

“C₁-C₈-alkoxy” as used herein denotes straight chain or branched alkoxyhaving 1 to 8 carbon atoms. Preferably, C₁-C₈-alkoxy is C₁-C₄-alkoxy.

“C₁-C₈-haloalkoxy” as used herein denotes C₁-C₈-alkoxy as hereinbeforedefined substituted by one or more halogen atoms, preferably one, two orthree halogen atoms. Preferably “C₁-C₈-haloalkoxy” is“C₁-C₄-haloalkoxy”.

“di(C₁-C₈-alkyl)sulfamoyl” as used herein denotes —SO₂—NH₂ where thenitrogen atom is substituted at two positions by C₁-C₈-alkyl ashereinbefore defined, which may be the same or different. Preferablydi(C₁-C₈-alkyl)sulfamoyl is —SO₂—N(CH₃)₂.

“Halo” or “halogen” as used herein denotes a element belonging to group17 (formerly group VII) of the Periodic Table of Elements, which may be,for example, fluorine, chlorine, bromine or iodine. Preferably halo orhalogen is fluorine, chlorine or bromine.

“Aminocarbonyl” as used herein denotes amino attached through thenitrogen atom to a carbonyl group.

“4- to 12-membered heterocyclic group containing at least one ringheteroatom selected from nitrogen, oxygen and sulphur” as used hereindenotes a monoheterocyclic, biheterocyclic or triheterocyclic group,which may be saturated or unsaturated, that has 4 to 12 ring atoms.Monoheterocyclic groups include azetidinyl, tetrahydrofuranyl, furyl,pyrrolyl, pyrrolidinyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thienyl, thiazolyl, thiadiazolyl, isothiazolyl, oxadiazolyl, pyridinyl,oxazolyl, isoxazolyl, piperidinyl, pyridinyl, pyrazinyl, pyridazinyl,pyrimidinyl, piperazinyl, morpholinyl, triazinyl, oxazinyl, thiazolyl ortetrahydropyranyl. Biheterocyclic groups include thienothienyl,benzazolyl, benzothienyl, benzimidazolyl, benzodioxinyl, indazolyl,benzothiazolyl, imidazopyridinyl and naphthyridinyl. Preferred 4- to12-membered heterocyclic groups include azetidinyl, tetrahydrofuranyl,furyl, pyrrolyl, pyrazolyl, triazolyl, thienyl, thiazolyl, thiadiazolyl,oxazolyl, isoxazolyl, tetrahydropyranyl, piperidinyl, pyridinyl,pyrazinyl, pyrimidinyl, thienothienyl, benzazolyl, benzothienyl,benzimidazolyl, benzodioxinyl, indazolyl and benzothiazolyl,imidazopyridinyl, naphthyridinyl. The 4- to 12-membered heterocyclicgroup can be unsubstituted or substituted at one or more positions, e.g.1, 2 or 3 positions, by any one or any combination of substituents.Preferred substituents include halo (e.g. fluoro, chloro or bromo),cyano, oxo, hydroxy, carboxy, nitro, C₁-C₈-alkyl (e.g. methyl or ethyl),halo-C₁-C₈-alkyl (e.g. trifluoromethyl), C₁-C₈-alkylcarbonyl,di(C₁-C₈-alkyl)sulfamoyl and C₁-C₈-alkoxy optionally substituted byaminocarbonyl. Especially preferred substituents include halo, oxo,C₁-C₄-alkyl and C₁-C₄-alkylcarbonyl.

Throughout this specification and in the claims that follow, unless thecontext requires otherwise, the word “comprise”, or variations such as“comprises” or “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

In a second aspect the invention provides compounds of formula I

in salt or zwitterionic form whereinR¹ and R³ are each independently a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—;R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyl optionallysubstituted by hydroxy;R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹, —O—CO—NHR¹², —O—CO—R¹³ or —CO—O—R¹⁴, orR⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;R⁵ is hydrogen or C₁-C₈-alkyl;R⁶ is C₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in eachcase optionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur;R⁷ is a C₃-C₁₅-carbocyclic group;R⁸ is a C₃-C₁₅-carbocyclic group;R⁹ is hydrogen or C₁-C₈-alkyl;R¹⁰ is hydrogen, C₁-C₈-alkyl optionally substituted by cyano, amino,nitro, carboxy, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group, or by a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;R¹¹ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkyl-C₁-C₈-alkoxy orC₁-C₈-alkyl-O—R¹³;R¹² is a C₃-C₁₅-carbocyclic group;R¹³ is C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group;R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group, or C₁-C₈-alkyl optionallysubstituted by a C₃-C₁₅-carbocyclic group; andR¹⁵ is a C₃-C₁₅-carbocyclic group.

In a third aspect the invention provides compounds of formula I

in salt or zwitterionic form whereinR¹ and R³ are each independently a C₃-C₁₅-carbocyclic group or a 5- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—;R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyl optionallysubstituted by hydroxy;R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NRS—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹, —O—CO—NHR¹², —O—CO—R¹³ or —CO—O—R¹⁴, orR⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 5- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;R⁵ is hydrogen or C₁-C₈-alkyl;R⁶ is C₁-C₈-alkyl or C₁-C₈-alkoxy in either case optionally substitutedby a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,or R⁶ is a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;R⁷ is a C₃-C₁₅-carbocyclic group;R⁸ is a C₃-C₁₋₅-carbocyclic group;R⁹ is hydrogen or C₁-C₈-alkyl;R¹⁰ is hydrogen, C₁-C₈-alkyl optionally substituted by cyano, amino,nitro, carboxy, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group, or by a 5- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur;R¹¹ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkyl-C₁-C₈-alkoxy orC₁-C₈-alkyl-O—R¹⁵;

-   R¹² is a C₃-C₁₅-carbocyclic group;    R¹³ is C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group;    R¹⁴ is hydrogen, C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group; and    R¹⁵ is a C₃-C₁₅-carbocyclic group.

Preferred compounds include those of formula I in salt or zwitterionicform, where R¹ and R³ are each independently a C₃-C₁₅-carbocyclic groupor a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R⁵ is hydrogen or C₁-C₈-alkyl;

R⁶ is C₁-C₈-alkyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in each caseoptionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,

or R⁶ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R⁷ is a C₃-C₁₅-carbocyclic group;

R⁸ is a C₃-C₁₅-carbocyclic group;

R⁹ is hydrogen or C₁-C₈-alkyl;

R¹⁰ is C₁-C₈-alkyl optionally substituted by cyano, C₁-C₈-alkoxy, aC₃-C₁₅-carbocyclic group or by a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R¹² is a C₃-C₁₅-carbocyclic group;

R¹³ is C₁-C₈-alkyl; and

R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group, C₁-C₈-alkenyl, orC₁-C₈-alkyl optionally substituted by a C₃-C₁₅-carbocyclic group.

Preferred compounds include those of formula I in salt or zwitterionicform, where R¹ and R³ are each independently a C₃-C₁₋₅-carbocyclic groupor a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NRS—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 4- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R⁵ is hydrogen or C₁-C₈-alkyl;

R⁶ is C₁-C₈-alkyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in each caseoptionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur,

or R⁶ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R⁷ is a C₃-C₁₅-carbocyclic group;

R⁸ is a C₃-C₁₅-carbocyclic group;

R⁹ is hydrogen or C₁-C₈-alkyl;

R¹⁰ is C₁-C₈-alkyl optionally substituted by cyano, C₁-C₈-alkoxy, aC₃-C₁₅-carbocyclic group or by a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R¹² is a C₃-C₁₅-carbocyclic group;

R¹³ is C₁-C₈-alkyl; and

R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group or C₁-C₈-alkyl optionallysubstituted by a C₃-C₁₅-carbocyclic group.

Preferred compounds also include those of formula I in salt orzwitterionic form, where R¹ and R³ are each independently aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁷—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclicgroup or a 5- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R⁵ is hydrogen;

R⁶ is C₁-C₈-alkyl or C₁-C₈-alkoxy in either case optionally substitutedby a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R⁶ is a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R⁷ is a C₃-C₁₅-carbocyclic group;

R⁸ is a C₃-C₁₅-carbocyclic group;

R⁹ is hydrogen or C₁-C₈-alkyl;

R¹⁰ is C₁-C₈-alkyl optionally substituted by cyano, C₁-C₈-alkoxy, aC₃-C₁₅-carbocyclic group or by a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R¹² is a C₃-C₁₅-carbocyclic group;

R¹³ is C₁-C₈-alkyl; and

R¹⁴ is hydrogen, C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group.

Especially preferred compounds include those of formula I in salt orzwitterionic form where R¹ and R³ are each independently aC₆-C₁₀-carbocyclic aromatic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₈-alkynyl optionally substituted by a C₃-C₁₀-carbocyclicgroup or a 4- to 10-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R⁵ is hydrogen or C₁-C₄-alkyl;

R⁶ is C₁-C₄-alkyl, C₂-C₈-alkynyl or C₁-C₄-alkoxy in each case optionallysubstituted by a C₃-C₁₀-carbocyclic group or a 4- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur,

or R⁶ is a C₃-C₁₀-carbocyclic group or a 4- to 10-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R⁷ is a C₃-C₁₀-carbocyclic group;

R⁸ is a C₃-C₁₀-carbocyclic group;

R⁹ is hydrogen or C₁-C₄-alkyl;

R¹⁰ is C₁-C₄-alkyl optionally substituted by cyano, C₁-C₄-alkoxy, aC₃-C₁₀-carbocyclic group or by a 4- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R¹⁰ is a C₃-C₁₀-carbocyclic group or a 4- to 10-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R¹² is a C₃-C₁₀-carbocyclic group;

R¹³ is C₁-C₄-alkyl; and

R¹⁴ is hydrogen, a C₃-C₁₀-carbocyclic group, C₁-C₄-alkenyl, orC₁-C₄-alkyl optionally substituted by a C₃-C₁₀-carbocyclic group.

Especially preferred compounds include those of formula I in salt orzwitterionic form where R¹ and R³ are each independently aC₆-C₁₀-carbocyclic aromatic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₈-alkynyl optionally substituted by a C₃-C₁₀-carbocyclicgroup or a 4- to 10-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

-   R⁵ is hydrogen or C₁-C₄-alkyl;    R⁶ is C₁-C₄-alkyl, C₂-C₈-alkynyl or C₁-C₄-alkoxy in each case    optionally substituted by a C₃-C₁₀-carbocyclic group or a 4- to    12-membered heterocyclic group having at least one ring heteroatom    selected from nitrogen, oxygen and sulphur,    or R⁶ is a C₃-C₁₀-carbocyclic group or a 4- to 10-membered    heterocyclic group having at least one ring heteroatom selected from    nitrogen, oxygen and sulphur;    R⁷ is a C₃-C₁₀-carbocyclic group;    R⁸ is a C₃-C₁₀-carbocyclic group;    R⁹ is hydrogen or C₁-C₄-alkyl;    R¹⁰ is C₁-C₄-alkyl optionally substituted by cyano, C₁-C₄-alkoxy, a    C₃-C₁₀-carbocyclic group or by a 4- to 10-membered heterocyclic    group having at least one ring heteroatom selected from nitrogen,    oxygen and sulphur,    or R¹⁰ is a C₃-C₁₀-carbocyclic group or a 4- to 10-membered    heterocyclic group having at least one ring heteroatom selected from    nitrogen, oxygen and sulphur;    R¹² is a C₃-C₁₀-carbocyclic group;    R¹³ is C₁-C₄-alkyl; and    R¹⁴ is hydrogen, a C₃-C₁₀-carbocyclic group or C₁-C₄-alkyl    optionally substituted by a C₃-C₁₀-carbocyclic group.

Especially preferred compounds also include those of formula I in saltor zwitterionic form where

R¹ and R³ are each independently a C₆-C₁₀-carbocyclic aromatic group ora 5- to 12-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R² is halo or hydroxy;

R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R¹², —O—CO—R¹³ or —CO—O—R¹⁴,

or R⁴ is C₃-C₈-alkynyl optionally substituted by a C₃-C₁₀-carbocyclicgroup or a 5- to 10-membered heterocyclic group having at least one ringheteroatom selected from nitrogen, oxygen and sulphur;

R⁵ is hydrogen;

R⁶ is C₁-C₄-alkyl or C₁-C₄-alkoxy in either case optionally substitutedby a C₃-C₁₀-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R⁶ is a C₃-C₁₀-carbocyclic group or a S— to 10-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R⁷ is a C₃-C₁₀-carbocyclic group;

R⁸ is a C₃-C₁₀-carbocyclic group;

R⁹ is hydrogen or C₁-C₄-alkyl;

R¹⁰ is C₁-C₄-alkyl optionally substituted by cyano, C₁-C₄-alkoxy, aC₃-C₁₀-carbocyclic group or by a 5- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur,

or R¹⁰ is a C₃-C₁₀-carbocyclic group or a 5- to 10-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur;

R¹² is a C₃-C₁₀-carbocyclic group;

R¹³ is C₁-C₄-alkyl; and

R¹⁴ is hydrogen, C₁-C₄-alkyl or a C₃-C₁₀-carbocyclic group.

The compounds of formula I are quaternary ammonium salts. Suitablecounter ions are pharmaceutically acceptable counter ions including, forexample, fluoride, chloride, bromide, iodide, nitrate, sulfate,phosphate, formate, acetate, trifluoroacetate, propionate, butyrate,lactate, citrate, tartrate, malate, maleate, succinate, benzoate,p-chlorobenzoate, diphenylacetate or triphenylacetate,o-hydroxybenzoate, p-hydroxybenzoate,1-hydroxynaphthalene-2-carboxylate, 3-hydroxynaphthalene-2-carboxylate,methanesulfonate and benzenesulfonate.

Compounds of formula I that contain a basic centre are capable offorming acid addition salts, particularly pharmaceutically acceptableacid addition salts. Pharmaceutically acceptable acid addition salts ofthe compound of formula I include those of inorganic acids, for example,hydrohalic acids such as hydrofluoric acid, hydrochloric acid,hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid,phosphoric acid; and organic acids, for example aliphatic monocarboxylicacids such as formic acid, acetic acid, trifluoroacetic acid, propionicacid and butyric acid, aliphatic hydroxy acids such as lactic acid,citric acid, tartaric acid or malic acid, dicarboxylic acids such asmaleic acid or succinic acid, aromatic carboxylic acids such as benzoicacid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid,aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoicacid, 1-hydroxynaphthalene-2-carboxylic acid or3-hydroxynaphthalene-2-carboxylic acid, and sulfonic acids such asmethanesulfonic acid or benzenesulfonic acid. These salts may beprepared from compounds of formula I by known salt-forming procedures.

Compounds of formula I which contain acidic, e.g. carboxyl, groups, arealso capable of forming salts with bases, in particular pharmaceuticallyacceptable bases such as those well known in the art; suitable suchsalts include metal salts, particularly alkali metal or alkaline earthmetal salts such as sodium, potassium, magnesium or calcium salts, orsalts with ammonia or pharmaceutically acceptable organic amines orheterocyclic bases such as ethanolamines, benzylamines or pyridine.These salts may be prepared from compounds of formula I by knownsalt-forming procedures. Compounds of formula I that contain acidic,e.g. carboxyl, groups may also exist as zwitterions with the quaternaryammonium centre.

The compounds of the invention contain at least one asymmetric carbonatom and thus they exist in individual optically active isomeric formsor as mixtures thereof, e.g. as racemic mixtures. In cases whereadditional asymmetric centres exist the present invention also embracesboth individual optically active isomers as well as mixtures, e.g.diastereomeric mixtures, thereof.

Specific especially preferred compounds of the invention are thosedescribed hereinafter in the Examples. These have R stereochemistry atthe 3 position of the quinuclidine.

The invention also provides a process for the preparation of compoundsof formula I which comprises(i) (A) reacting a compound of compound of formula II

-   -   or a protected form thereof where R¹, R² and R³ are as        hereinbefore defined, with a compound of formula III        R¹—X  III    -   where R⁴ is as hereinbefore defined and X is chloro, bromo or        iodo;    -   (B) for the preparation of compounds of formula I where R⁴ is        C₁-C₈-alkyl substituted by —NR⁵—CO—R⁶ where R⁵ and R⁶ are as        hereinbefore defined, reacting a compound of formula IV    -   or a protected form thereof where R¹, R², R³ and R⁵ are as        hereinbefore defined, optionally in the presence of a coupling        agent, and T denotes C₁-C₈-alkylene, with a compound of formula        V    -   where R⁶ is as hereinbefore defined or an amide-forming        derivative thereof such as an acid halide;    -   (C) for the preparation of compounds of formula I where R⁴ is        C₁-C₈-alkyl substituted by —NR⁵—CO—NH—R⁷ where R⁵ and R⁷ are as        hereinbefore defined, reacting a compound of formula IV or a        protected form thereof where R¹, R², R³ and R⁵ are as        hereinbefore defined and T denotes C₁-C₈-alkylene, with a        compound of formula VI        O═C═N—R⁷  VI    -   where R⁷ is as hereinbefore defined;    -   (D) for the preparation of compounds of formula I where R⁴ is        C₁-C₈-alkyl substituted by —NR⁵—SO₂—R⁸ where R⁵ and R⁸ are as        hereinbefore defined, reacting a compound of formula IV or a        protected form thereof where R¹, R², and R³ are as hereinbefore        defined and T denotes C₁-C₈-alkylene, with a compound of formula        VII    -   where R⁸ is as hereinbefore defined and X is halo; or    -   (E) for the preparation of compounds of formula I where R⁴ is        C₁-C₈-alkyl substituted by —CO—NR⁹R¹⁰ where R⁹ and R¹⁰ are as        hereinbefore defined, reacting a compound of formula VIII    -   or a protected form thereof where R¹, R², and R³ are as        hereinbefore defined and T denotes C₁-C₈-alkylene, optionally in        the presence of a coupling agent, or an amide-forming derivative        thereof such as an acid halide, with a compound of formula IX    -   where R⁹ and R¹⁰ are as hereinbefore defined; and        (ii) recovering the product in salt or zwitterionic form.

Process variant (A) may be effected using known procedures for reactingquinuclidinol esters with halogenides or analogously as hereinafterdescribed in the Examples. The reaction is conveniently carried out inwater or an organic solvent, for example acetonitrile, dimethylformamide(DMF), dimethylsulphoxide (DMSO), ethyl acetate or chloroform. Thereaction is carried out at a temperature between 20° C. to 120° C.,conveniently between room temperature and 80° C.

Process variant (B) may be effected using known procedures for reactingamines with carboxylic acids or amide-forming derivatives thereof suchas acid halides to give amides or analogously as hereinafter describedin the Examples. The reaction between the carboxylic acid and the amineis conveniently carried out in an organic solvent, for exampledimethylformamide (DMF), optionally in the presence of a coupling agent,for example O-(7-azabenzotriazol-1-yl)-N,N,—N′,N′-tetramethyl-uroniumhexafluorophophate (HATU), and a base, for examplediisopropyl-ethylamine (DIPEA) or triethylamine. Suitable reactiontemperatures are from 0° C. to 50° C., conveniently room temperature.

Process variant (C) may be effected using known procedures for reactingamines with isocyanates to give ureas or analogously as hereinafterdescribed in the Examples. The reaction is conveniently carried out inan organic solvent, for example dimethylformamide (DMF), and preferablyin the presence of a base, for example DIPEA. Suitable reactiontemperatures are from −78° C. to 40° C., conveniently room temperature.

Process variant (D) may be effected using known procedures for reactingamines with sulfonylhalides to give sulfonamides or analogously ashereinafter described in the Examples. The reaction is convenientlycarried out in an organic solvent, for example dimethylformamide (DMF),and preferably in the presence of a base, for example DIPEA. Suitablereaction temperatures are from 0° C. to 50° C., conveniently roomtemperature.

Process variant (E) may be effected using known procedures for reactingcarboxylic acids or amide-forming derivatives thereof such as acidhalides with amines to give amides or analogously as hereinafterdescribed in the Examples. The reaction between the carboxylic acid andthe amine is conveniently carried out in an organic solvent, for exampledimethylsulfoxide (DMSO) or dimethylformamide (DMF), optionally in thepresence of a coupling agent, for example HATU, and preferably in thepresence of a base, for example DIPEA. Suitable reaction temperaturesare from 0° C. to 50° C., conveniently room temperature.

Compounds of formula II are known or may be prepared by known proceduressuch as those disclosed in W. J. Rzeszotarski et al, J. Med. Chem. 1988,31, 1463, international patent publication WO 01/04118 and U.S. Pat. No.3,833,592.

Compounds of formula III are known or may be prepared by knownprocedures.

Compounds of formula IV may be prepared by deprotecting a compound offormula X

where R¹, R², R³ and R⁵ are as hereinbefore defined, Q is an amineprotecting group and T denotes C₁-C₈-alkylene, e.g. when Q ist-butyloxycarbonyl by treatment with a strong acid, e.g. hydrochloricacid or hydrobromic acid, which is conveniently carried out in anorganic solvent, for example dioxan (1,4-dioxycyclohexane), and suitablereaction temperatures are from 0° C. to 60° C., conveniently roomtemperature.

Compounds of formula V, VI and VII are known or may be prepared by knownprocedures.

Compounds of formula VIII may be prepared by cleavage of a correspondingester of formula XI

where R¹, R², and R³ are as hereinbefore defined, T denotesC₁-C₈-alkylene and W denotes a group that is readily replaceable byhydrogen. For example when W is t-butyl the compound may be reacted withan anhydrous strong acid, e.g. hydrochloric acid, hydrobromic acid ortrifluoroacetic acid, which is conveniently carried out in an organicsolvent, for example dioxane, and suitable reaction temperatures arefrom −20° C. to 40° C., conveniently room temperature.

Compounds of formula IX are known or may be prepared by knownprocedures.

Compounds of formula X may be prepared by reacting a compound of formulaII where R¹, R² and R³ are as hereinbefore defined, with a compound offormula XII

where R⁵ is as hereinbefore defined, Q is an amine protecting group e.g.t-butyloxycarbonyl, X¹ is chloro, bromo or iodo and T denotesC₁-C₈-alkylene. The reaction is conveniently carried out in an organicsolvent, for example DMF. Suitable reaction temperatures are from 40° C.to 120° C., conveniently between room temperature and 80° C.

Compounds of formula XI may be prepared by reacting a compound offormula II where R¹, R² and R³ are as hereinbefore defined, with acompound of formula XIII

where T denotes C₁-C₈-alkylene, X² is chloro, bromo or iodo and W is agroup that is readily replaceable by hydrogen. For example when W ist-butyl the reaction is conveniently carried out in an organic solvent,for example DMF. Suitable reaction temperatures are from 0° C. to 120°C., conveniently between room temperature and 60° C.

Compounds of formula XII and XIII are known or may be prepared by knownprocedures.

Where reference is made herein to protected functional groups or toprotecting groups, the protecting groups may be chosen in accordancewith the nature of the functional group, for example as described inProtective Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts,John Wiley & Sons Inc, Third Edition, 1999, which reference alsodescribes procedures suitable for replacement of the protecting groupsby hydrogen.

Compounds of formula I are quaternary ammonium salts and may beconverted between different salt forms using ion exchangechromatography. The compounds can be obtained in the form of hydrates orsolvates containing a solvent used for crystallization. Compounds offormula I can be recovered from reaction mixtures and purified usingknown methods. Isomers, such as enantiomers, may be obtained in aconventional manner, e.g. by fractional crystallization, chiral phasechromatography or asymmetric synthesis from correspondinglyasymmetrically substituted, e.g. optically active, starting materials.

Compounds of formula I in pharmaceutically acceptable salt orzwitterionic form, hereinafter referred to alternatively as agents ofthe invention, are useful as pharmaceuticals. Accordingly the inventionalso provides a compound of formula I in pharmaceutically acceptablesalt or zwitterionic form for use as a pharmaceutical. The agents of theinvention act as muscarinic antagonists, particularly muscarinic M3receptor antagonists, thereby inhibiting acetylcholine-inducedcontraction of smooth muscle in e.g. respiratory tract, digestive tractand urinary systems.

The affinity (Ki) of agents of the invention at the human muscarinicacetylcholine M3 receptor can be determined in a competitive filtrationbinding assay with the radio-labelled antagonist [³H] n-methylscopolamine methyl chloride (NMS):

Membranes prepared from CHO cells stably transfected with human M3receptor at 10 μg protein/well are incubated with serial dilutions ofthe agents of the invention, [³H]NMS (0.25 nM) and assay buffer (20 mMHEPES, 1 mM MgCl₂ at pH 7.4) for 17 hours at room temperature. The assayis carried out in a 250 μL final volume, in the presence of a finaldimethyl sulfoxide concentration of 1%. Total binding of [³H]NMS isdetermined in the absence of the agents of the invention with acorresponding substituted volume of assay buffer. Non-specific bindingof [³H] NMS is determined in the presence of 300 nM ipratropium bromide.Following the incubation period, the membranes are harvested onto aUnifilter™ GF/B filter plate containing 0.05% polyethyleneimine, using aBrandel™ filtration harvester 9600. Filter plates are dried for twohours at 35° C. before the addition of Microscint™ ‘O’ cocktail, andread on a Packard Topcount™ scintillator using a ³H-Scintillationprotocol. All IC50s are calculated with the aid of XL-Fit graph packageand K_(i) values derived using the Cheng-Prusoff correction (Cheng Y.,Prusoff W. H. (1973) Biochem. Pharmacol 22 3099-3109).

The compounds of the Examples herein below generally have Ki valuesbelow 1 μM in the above assay. For instance, the compounds of Examples17, 34, 52, 54, 71, 76, 96, 114, 138, 159, 170, 190, 209, 221, 242 and244 have M3 K_(i) values of 0.0144, 0.0023, 0.0019, 0.0001, 0.0005,0.0011, 0.0046, 0.0002, 0.0022. 0.0007, 0.0007, 0.0007, 0.0010, 0.0013,0.0003 and 0.0003 μM respectively.

Having regard to their inhibition of acetyl choline binding to M3muscarinic receptors, agents of the invention are useful in thetreatment of conditions mediated by the muscarinic M3 receptor,particularly those associated with increased parasympathetic toneleading to, for example, excessive glandular secretion or smooth musclecontraction. Treatment in accordance with the invention may besymptomatic or prophylactic.

Having regard to their antimuscarinic activity, the agents of theinvention are useful in the relaxation of bronchial smooth muscle andthe relief of bronchoconstriction. Relief of bronchoconstriction can bemeasured in models such as the in vivo plethysmography models of Chonget al, J. Pharmacol. Toxicol. Methods 1998, 39, 163, Hammelmann et al,Am. J. Respir. Crit. Care Med., 1997, 156, 766 and analogous models. Theagents of the invention are therefore useful in the treatment ofobstructive or inflammatory airways diseases. In view of their longduration of action, it is possible to administer the agents of theinvention once-a-day in the treatment of such diseases. In anotheraspect, agents of the invention commonly exhibit characteristicsindicating a low incidence of side effects commonly encountered with β₂agonists such as tachycardia, tremor and restlessness, such agentsaccordingly being suitable for use in on demand (rescue) treatment aswell as prophylactic treatment of obstructive or inflammatory airwaysdiseases.

Inflammatory or obstructive airways diseases to which the presentinvention is applicable include asthma of whatever type or genesisincluding both intrinsic (non-allergic) asthma and extrinsic (allergic)asthma. Treatment of asthma is also to be understood as embracingtreatment of subjects, e.g. of less than 4 or 5 years of age, exhibitingwheezing symptoms and diagnosed or diagnosable as “wheezy infants”, anestablished patient category of major medical concern and now oftenidentified as incipient or early-phase asthmatics. (For convenience thisparticular asthmatic condition is referred to as “wheezy-infantsyndrome”.)

Prophylactic efficacy in the treatment of asthma will be evidenced byreduced frequency or severity of symptomatic attack, e.g. of acuteasthmatic or bronchoconstrictor attack, improvement in lung function orimproved airways hyperreactivity. It may further be evidenced by reducedrequirement for other, symptomatic therapy, i.e. therapy for or intendedto restrict or abort symptomatic attack when it occurs, for exampleanti-inflammatory (e.g. corticosteroid) or bronchodilatory. Prophylacticbenefit in asthma may in particular be apparent in subjects prone to“morning dipping”. “Morning dipping” is a recognised asthmatic syndrome,common to a substantial percentage of asthmatics and characterised byasthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a timenormally substantially distant from any previously administeredsymptomatic asthma therapy.

Other inflammatory or obstructive airways diseases and conditions towhich the present invention is applicable include adult/acuterespiratory distress syndrome (ARDS), chronic obstructive pulmonary orairways disease (COPD or COAD), including chronic bronchitis, or dyspneaassociated therewith, emphysema, as well as exacerbation of airwayshyperreactivity consequent to other drug therapy, in particular otherinhaled drug therapy. The invention is also applicable to the treatmentof bronchitis of whatever type or genesis including, e.g., acute,arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Furtherinflammatory or obstructive airways diseases to which the presentinvention is applicable include pneumoconiosis (an inflammatory,commonly occupational, disease of the lungs, frequently accompanied byairways obstruction, whether chronic or acute, and occasioned byrepeated inhalation of dusts) of whatever type or genesis, including,for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis,siderosis, silicosis, tabacosis and byssinosis.

Having regard to their antimuscarinic activity, the agents of theinvention are also useful in the treatment of a condition requiringrelaxation of smooth muscle of the uterus, bladder or vascular system.They are thus useful for the prevention or alleviation of prematurelabour pains in pregnancy. They are also useful in the treatment ofchronic and acute urticaria, psoriasis, allergic conjunctivitis,actinitis, rhinitis including allergic rhinitis, mastocytosis, urinarydisorders such as urinary incontinence (particularly that caused byoveractive bladder), pollakiuria, neurogenic or unstable bladder,cytospasm and chronic cystitis; gastrointestinal disorders such asirritable bowel syndrome, spastic colitis, diverticulitis and pepticulceration; and cardiovascular disorders such as vagally induced sinusbradycardia, as well as in ophthalmic interventions.

The agents of the invention are also useful as co-therapeutic agents foruse in combination with other drug substances such as anti-inflammatory,bronchodilatory, antihistamine, decongestant or anti-tussive drugsubstances, particularly in the treatment of obstructive or inflammatoryairways diseases such as those mentioned hereinbefore, for example aspotentiators of therapeutic activity of such drugs or as a means ofreducing required dosaging or potential side effects of such drugs. Anagent of the invention may be mixed with one or more other drugsubstances in a fixed pharmaceutical composition or it may beadministered separately, before, simultaneously with or after the otherdrug substance(s). Accordingly the invention includes a combination ofan agent of the invention as hereinbefore described with ananti-inflammatory, bronchodilatory, antihistamine, decongestant oranti-tussive drug substance, said agent of the invention and said drugsubstance being in the same or different pharmaceutical composition.Such anti-inflammatory drugs include steroids, for exampleglucocorticosteroids such as budesonide, beclamethasone, fluticasone,ciclesonide or mometasone, or steroids described in WO 02/88167, WO02/12266, WO 02/100879 or WO 02/00679, especially those of Examples 3,11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101, andnon-steroidal steroid agonists such as those described in WO 00/00531,WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229;LTB4 antagonists such as those described in U.S. Pat. No. 5,451,700;LTD4 antagonists such as montelukast and zafirlukast; PDE4 inhibitorssuch as cilomilast (Ariflo® GlaxoSmithKline), Roflumilast (Byk Gulden),V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough),Arofylline (Almirall Prodesfarma), PD189659 (Parke-Davis), AWD-12-281(Asta Medica), CDC-801 (Celgene), SelCID(TM) CC-10004 (Celgene), KW-4490(Kyowa Hakko Kogyo), WO 03/104204, WO 03/104205, WO 04/000814, WO04/000839 and WO 04005258 (Merck), as well as those described in WO98/18796 and WO 03/39544; A2a agonists such as those described in EP1052264, EP 1241176, EP 409595A2, WO 94/17090, WO 96/02543, WO 96/02553,WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO00/23457, WO 00/77018, WO 00/78774, WO 01/23399, WO 01/27130, WO01/27131, WO 01/60835, WO 01/94368, WO 02/00676, WO 02/22630, WO02/96462, and WO 03/086408; and A2b antagonists such as those describedin WO 02/42298.

The agents of the invention are useful in combination therapy withchemokine receptor antagonists, calcium channel blockers,alpha-adrenoceptor antagonists, dopamine agonists, endothelinantagonists, substance-P antagonists, 5-LO inhibitors, VLA-4 antagonistsand theophylline.

The agents of the invention are also particularly useful asco-therapeutic agents for use in combination with beta-2 adrenoceptoragonists or corticosteroids. Suitable beta-2 adrenoceptor agonistsinclude salbutamol, terbutaline, salmeterol and, especially, formoteroland pharmaceutically acceptable salts thereof, and compounds (in free orsalt or solvate form) of formula I of WO 0075114, which document isincorporated herein by reference, preferably compounds of the Examplesthereof, especially a compound of formula

and pharmaceutically acceptable salts thereof, as well as compounds (infree or salt or solvate form) of formula I of WO 04/16601.

Co-therapeutic antihistamine drug substances include cetirizinehydrochloride, acetaminophen, clemastine fumarate, promethazine,loratidine, desloratidine, diphenhydramine and fexofenadinehydrochloride.

Combinations of agents of the invention and one or more of beta-2adrenoceptor agonists, steroids, PDE4 inhibitors, A2a agonists, A2bagonists and LTD4 antagonists may be used, for example, in the treatmentof asthma but particularly COPD.

In accordance with the foregoing, the present invention also provides amethod for the treatment of an obstructive or inflammatory airwaysdisease which comprises administering to a subject, particularly a humansubject, in need thereof a compound of formula I, or a pharmaceuticallyacceptable salt or solvate thereof, as hereinbefore described. Inanother aspect, the invention provides a compound of formula I, or apharmaceutically acceptable salt or solvate thereof, as hereinbeforedescribed for use in the preparation of a medicament for the treatmentof an obstructive or inflammatory airways disease.

The agents of the invention may be administered by any appropriateroute, e.g. orally, for example in the form of a tablet or capsule;parenterally, for example intravenously; topically to the skin, forexample in the treatment of psoriasis; intranasally, for example in thetreatment of hay fever; or, preferably, by inhalation, particularly inthe treatment of obstructive or inflammatory airways diseases. Inparticular, the agents of the invention may be delivered as an inhalableformulation for the treatment of COPD and asthma.

In a further aspect, the invention also provides a pharmaceuticalcomposition comprising a compound of formula I in free form or in theform of a pharmaceutically acceptable salt or solvate thereof,optionally together with a pharmaceutically acceptable diluent orcarrier thereof. Such compositions may be prepared using conventionaldiluents or excipients and techniques known in the galenic art. Thusoral dosage forms may include tablets and capsules. Formulations fortopical administration may take the form of creams, ointments, gels ortransdermal delivery systems, e.g. patches. Compositions for inhalationmay comprise aerosol or other atomizable formulations or dry powderformulations.

When the composition comprises an aerosol formulation, it preferablycontains, for example, a hydro-fluoro-alkane (HFA) propellant such asHFA134a or HFA227 or a mixture of these, and may contain one or moreco-solvents known in the art such as ethanol (up to 20% by weight),and/or one or more surfactants such as oleic acid or sorbitan trioleate,and/or one or more bulking agents such as lactose. When the compositioncomprises a dry powder formulation, it preferably contains, for example,the compound of formula I having a particle diameter up to 10 microns,optionally together with a diluent or carrier, such as lactose, of thedesired particle size distribution and a compound that helps to protectagainst product performance deterioration due to moisture. When thecomposition comprises a nebulised formulation, it preferably contains,for example, the compound of formula I either dissolved, or suspended,in a vehicle containing water, a co-solvent such as ethanol or propyleneglycol and a stabiliser, which may be a surfactant.

The invention also includes (A) a compound of formula I as hereinbeforedescribed in free form, or a pharmaceutically acceptable salt or solvatethereof, in inhalable form; (B) an inhalable medicament comprising sucha compound in inhalable form together with a pharmaceutically acceptablecarrier in inhalable form; (C) a pharmaceutical product comprising sucha compound in inhalable form in association with an inhalation device;and (D) an inhalation device containing such a compound in inhalableform.

Dosages of agents of the invention employed in practising the presentinvention will of course vary depending, for example, on the particularcondition to be treated, the effect desired and the mode ofadministration. In general, suitable daily dosages for administration byinhalation are of the order of 0.0001 to 30 mg/kg, typically 0.01 to 10mg per patient, while for oral administration suitable daily doses areof the order of 0.01 to 100 mg/kg.

The invention is illustrated by the following Examples.

EXAMPLES

Especially preferred compounds of formula I include compounds of formulaXIV

where R¹, R², R³, and R⁴ are as shown in Table 1 below, the method ofpreparation being described hereinafter. All compounds are quaternaryammonium salts. The table also shows mass spectrometry data. TABLE 1 M/sEx. R¹ and R³ R⁴ R² M+ 1

OH 395.4 2

OH 499.4 3

OH 549.5 4

OH 524.5 5

OH 527.5 6

OH 575.5 7

OH 564.5 8

OH 577.5 9

OH 500.4 10

OH 533.4 11

OH 559.4 12

OH 533.4 13

OH 527.4 14

OH 567.4 15

OH 567.4 16

OH 567.4 17

OH 559.5 18

OH 529.4 19

OH 529.4 20

OH 557.5 21

OH 559.5 22

OH 559.5 23

OH 524.4 24

OH 547.4 25

OH 524.4 26

OH 529.5 27

OH 500.4 28

OH 500.4 29

OH 504.4 30

OH 505.7 31

OH 519.7 32

OH 491.7 33

OH 493.7 34

OH 513.7 35

OH 527.7 36

OH 548.7 37

OH 505.7 38

OH 501.6 39

OH 539.7 40

OH 514.7 41

OH 514.7 42

OH 544.6 43

OH 533.2 44

OH 577.2 45

OH 527.7 46

OH 465.6 47

OH 514.4 48

OH 584.3 49

OH 535.4 50

OH 485.4 51

OH 546.3 52

OH 471.4 53

OH 485.4 54

OH 376.3 55

OH 535.0 56

OH 390.3 57

OH 418.2 58

OH 452.2 59

OH 495.4 60

OH 452 61

OH 481 62

OH 396 63

OH 567 64

OH 404.2 65

OH 535.2 66

OH 507.4 67

OH 500.4 68

OH 506.5 69

OH 404.3 70

OH 507.3 71

OH 416.3 72

OH 519.4 73

OH 512.3 74

OH 388.2 75

OH 497.1 76

OH 483.3 77

OH 518.4 78

OH 558.3 79

OH 464.7 80

OH 475.2 81

OH 505.2 82

OH 539.2 83

OH 501.3 84

OH 505.2 85

OH 449.3 86

OH 516.3 87

OH 485.3 88

OH 519.2 89

OH 499.3 90

OH 511.3 91

OH 519.2 92

OH 519.2 93

OH 535.3 94

OH 520.3 95

OH 553.2 96

OH 505.3 97

OH 491.3 98

OH 437.3 99

OH 423.2 100

OH 449.2 101

OH 437.3 102

OH 477.3 103

OH 491.2 104

OH 453.3 105

OH 499.3 106

OH 448.3 107

OH 578.3 108

OH 495.3 109

F 474.3 110

F 378.2 111

F 426.3 112

OH 500.4 113

OH 402.3 114

OH 430 115

OH 535.2 116

OH 510.2 117

OH 513.3 118

OH 561.3 119

OH 550.2 120

OH 563.2 121

OH 486.2 122

OH 519.2 123

OH 545.2 124

OH 519.2 125

OH 513.2 126

OH 553.2 127

OH 553.2 128

OH 553.2 129

OH 545.2 130

OH 515.2 131

OH 515.2 132

OH 543.2 133

OH 545.2 134

OH 511.2 135

OH 515.3 136

OH 513.2 137

OH 491.3 138

OH 487.2 139

OH 525.2 140

OH 475.3 141

OH 520.2 142

OH 525.3 143

OH 491.3 144

OH 488.3 145

OH 503.3 146

OH 566.3 147

OH 507.2 148

OH 490.3 149

OH 489.3 150

OH 521.3 151

OH 535.3 152

OH 533.2 153

OH 525.2 154

OH 569.2 155

OH 503.3 156

OH 555.2 157

OH 503.3 158

OH 485.2Preparation of Specific Examples

Abbreviations used are as follows: DAST is diethylaminosulfurtrifluoride, DCE is dichloroethane, DCM is dichloromethane, DIPEA isdiisopropylethylamine, DME is dimethoxyethane, HATU isO-(7-azabenzotriazol-1-yl)-N,N, —N′,N′-tetramethyl-uroniumhexafluorophophate, HPLC is High Performance Liquid Chromatography,Isolute CBA is propylcarboxylic acid, NBS is N-bromosuccinimide, PyBOPis benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate andTHF is tetrahydrofuran. BEMP:2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine,polymer bound.

In cases where purification is performed by C18 reverse phase columnchromatography utilising trifluoroacetic acid as a component of theeluent, the composition of the resulting counter ion was not confirmedspectroscopically, and may indeed be a variable mixture oftrifluoroacetate and the halide resulting from the quaternarisationreaction. Where HATU is used as a coupling agent the counter ion mayalso be hexa fluorophosphate.

Example 1(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane

(i) Bromide:

To a stirred solution of hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (5 g, 14.82 mmol) in DMF (40ml) is added 3-aminopropyl bromide (pre-neutralised from 3-aminopropylbromide hydrobromide using polymer supported diethyl amine) (6.47 g,29.54 mmol). The reaction mixture is heated to 40° C. overnight and thenconcentrated in vacuo. The crude residue is diluted with acetonitrileand the resulting precipitate is filtered and redissolved in DMF (20ml). Merrifield resin is added to this solution followed by potassiumcarbonate (20 mg, catalytic amount) and the reaction is stirred at 40°C. for 24 hours. The reaction mixture is filtered and acetonitrile isadded to the filtrate. The resulting precipitate is filtered and driedin vacuo to yield the titled compound.

(ii) Chloride:

(a)(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (1g, 2.97 mmol) and 3-(BOC-amino)propylbromide (1.06 g, 4.73 mmol) aredissolved in DMF (10 ml) and stirred to 60° C. for 4 hours. The solventis removed in vacuo and purification of the crude residue bychromatography on C18 silica, eluting with water:acetonitrile affordsthe title compound as a colourless foam.

(b)(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride hydrochloride

To a stirred solution of(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide [Example 1(ii)(a)] (1 g, 2.02 mmol) in dioxane (10 ml) at roomtemperature is added hydrochloric acid (1.5 ml, 4M aqueous solution).The reaction mixture is stirred for 16 hours and the solvent is removedin vacuo to yield the titled compound as a white solid.

Example 2(R)-1-(3-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate

To a stirred solution of benzoic acid (0.012 g, 0.1 mmol) and HATU(0.038 g, 0.1 mmol) in DMF (0.5 ml) is added DIPEA (0.05 ml). Thereaction mixture is left to stand at room temperature for 15 minutesafter which time, a solution comprising(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride hydrochloride [Example 1(ii)] (0.047 g, 0.1 mmol) in DMF (0.5ml) is added. The reaction mixture is stirred at room temperature for 30minutes and the solvent is removed in vacuo. Purification by massdirected preparative HPLC eluting with acetonitrile: water:trifluoroacetic acid yields the titled compound as a colourless oil.

Examples 3 to 46

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(naphthalene-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(4-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(2,6-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[3-[(Biphenyl-4-carbonyl)-amino)-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-pyrrol-1-yl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methanesulfonyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-3-carbonyl)-amino]-propyl)-1-azonia-bicyclo-[2.2.2]octanetrifluoro-acetate,(R)-1-[3-(4-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(3,5-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[3-(3-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-1-[3-(4-Ethyl-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-trifluoromethyl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-trifluoromethyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-trifluoromethyl-benzoyl-amino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(3,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo-[2.2.2]octane-trifluoro-acetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(4-isopropoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(2,4-Dimethoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[3-(2,3-Dimethoxy-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoro-acetate,(R)-1-[3-(2-Cyano-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(3-Fluoro-4-methoxy-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-1-[3-(3-Cyano-benzoyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-methoxy-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{3-[(pyridine-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo[2.2.2]octane-trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(pyridine-4-carbonyl)-amino]-propyl)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(5-methyl-isoxazole-3-carbonyl)-amino]-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(Cyclohexanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[3-(Cycloheptanecarbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[3-(Cyclopentane-carbonyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(3,3-Dimethyl-butyrylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylacetylamino-propyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-propionylamino)-propyl]-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-(3-[(1-Acetyl-piperidine-4-carbonyl)-amino]-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(2-Cyclopentyl-acetylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-{3-[(pyrazine-2-carbonyl)-amino]-propyl}-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(indane-2-carbonyl)-amino]-propyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-pyridin-2-yl-acetylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-[(2-methyl-pyridine-3-carbonyl)amino]-propyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-nitro-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[3-(2-Chloro-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(2-methanesulfonyl-benzoylamino)-propyl]-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-1-[3-(3,5-Dimethyl-benzoylamino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-isobutyryl-amino-propyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate respectively, are all prepared by the procedure ofExample 2 from(R)-1-(3-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride [Example 1(ii)] and the appropriate acid.

Example 47(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl]-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate

To a solution comprising(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride [Example 1(ii)] (0.023 g, 0.05 mmol) and DIPEA (0.025 ml) inDMF (0.25 ml) is added phenyl isocyanate (0.006 ml). The reactionmixture is left to stand at room temperature overnight. Purificationusing mass directed preparative HPLC eluting with acetonitrile: water:trifluoroacetic acid affords the titled compound.

Example 48(R)-1-{3-[3-(4-Butyl-2-methyl-phenyl)-ureido]-propyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

This compound is made via an analogous procedure to(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(3-phenyl-ureido)-propyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 47) by replacing phenyl isocyanate with4-butyl-1-isocyanato-2-methyl-benzene.

Example 49(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2.]octanetrifluoroacetate (i)(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

To a stirred suspension of hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF (50ml) under an atmosphere of argon is added (2-Bromo-ethyl)-carbamic acidtert-butyl ester (2.5 g, 11.16 mmol). The reaction mixture is heated to60° C. overnight and then the solvent is removed in vacuo to yield abrown oil which is used crude in the next step.

(ii)(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide

To a stirred suspension of(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide (0.5 g, 1.04 mmol) in dioxane (25 ml) is added hydrogen bromidesolution in dioxane (1 ml, prepared by bubbling HBr gas through dry,cooled dioxane). The reaction mixture is stirred at room temperatureovernight. The solvent is removed in vacuo and purification of the cruderesidue by chromatography on C18 silica, eluting with water:acetonitrileaffords the title compound as a brown solid.

(iii)(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

A solution comprising(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide [Example 50(ii)] (0.032 g, 0.059 mmol)p-toluenesulfonyl chloride (0.011 g, 0.059 mmol) and DIPEA (0.041 ml,0.236 mmol) in DMF (0.5 ml) is allowed to stir at room temperature for66 hours. Purification using mass directed preparative HPLC eluting withacetonitrile: water: trifluoroacetic acid affords the titled compound.

Example 50(R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanebromide (i)(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

To a stirred suspension of hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.5 g, 7.42 mmol) in DMF (50ml) under an atmosphere of argon is added (2-Bromo-ethyl)-carbamic acidtert-butyl ester (2.5 g, 11.16 mmol). The reaction mixture is heated to60° C. overnight and then the solvent is removed in vacuo to yield abrown oil which is used crude in the next step.

(ii)(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide

To a stirred suspension of(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide (0.5 g, 1.04 mmol) in dioxane (25 ml) is added hydrogen bromidesolution in dioxane (1 ml, prepared by bubbling HBr gas through dry,cooled dioxane). The reaction mixture is stirred at room temperatureovernight. The solvent is removed in vacuo and purification of the cruderesidue by chromatography on C18 silica, eluting with water:acetonitrileaffords the title compound as a brown solid.

(iii)(R)-1-(2-Benzoylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanebromide

To a stirred suspension of(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide [50(ii)] (0.28 g, 0.517 mmol) in DCM at 0° C. isadded triethylamine (0.216 ml, 1.552 mmol) followed by benzoyl bromide(0.122 ml, 1.03 mmol). The reaction mixture is stirred at 0° C. for 1.5hours and the solvent was removed in vacuo. Purification of the cruderesidue by chromatography on C18 silica, eluting with water:acetonitrileaffords the title compound.

Example 51(R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester(0.050 g, 0.148 mmol), 2-Bromo-N-(5-fluoro-benzothiazol-2-yl)-acetamide(0.064 g, 0.222 mmol) and potassium carbonate (0.01 g, catalyticquantity) are added to DMSO (0.5 ml) and stirred together at 40° C.overnight. Purification using mass directed preparative HPLC elutingwith acetonitrile: water: trifluoroacetic acid affords the titledcompound.

Example 52(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octane

(i) Trifluoroacetate:

To a sealed vial containing hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.020 g, 0.059 mmol in DMSO) isadded 2-chloro-N-phenyl-acetamide (0.030 g, 0.177 mmol in methylenechloride. The reaction mixture is stirred at room temperature overnightand purification using mass directed preparative HPLC eluting withacetonitrile: water: trifluoroacetic acid affords the titled compound.

(ii) Chloride:

Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester(0.2 g, 0.593 mmol) and 2-chloro-N-phenyl-acetamide (0.12 g, 0.89 mmol)are added to DMSO (2 ml) and stirred at 40° C. overnight. The solvent inremoved in vacuo and purification by chromatography on C18 silicaeluting with water:acetonitrile yields the titled compound as a chloridesalt.

Example 53(R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate

The title compound is made via an analogous procedure to(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octanechloride [Example 52 (ii)] by replacing 2-chloro-N-phenyl-acetamide with3-chloro-N-phenyl-propionamide.

Examples 54 to 58

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-(3-Benzenesulfonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-But-2-ynyl-3-(2-hydroxy-2,2-dipheny]-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate, and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-azonia-bicycio[2.2.2]-octanetrifluoroacetate are prepared made via an analogous procedure to(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Example 52 (i)] by replacing2-chloro-N-phenyl-acetamide with the appropriate alkyl halide.

Example 59(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

Preparation of this compound is described in Example 1(ii)(a).

Example 60(R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanebromide

To a solution comprising hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.2 g, 0.593 mmol) in drychloroform (5 ml) is added t-butylbromoacetate (0.438 ml, 2.96 mmol).The reaction mixture is left to stand at room temperature overnight. Thesolvent is removed in vacuo and purification of the crude residue bychromatography on C18 silica, eluting with water:acetonitrile affordsthe title compound as a white solid.

Example 61(R)-1-(2-tert-Butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

The title compound is made via an analogous procedure to(R)-1-tert-butoxycarbonylmethyl-3(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide(Example 60) by replacing t-butylbromoacetate with(2-bromo-ethyl)-carbamic acid tert-butyl ester.

Example 62(R)-1-Carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate

To a stirred solution of(R)-1-tert-Butoxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide (Example 60) (0.14 g, 0.264 mmol) in chloroform (5 ml) is addedtrifluoroacetic acid (1 ml). The reaction mixture is left to stir atroom temperature overnight. The solvent is removed in vacuo andpurification of the residue by chromatography on C18 silica, elutingwith water:acetonitrile affords the titled compound as a white solid.

Example 63(R)-1-[(5,6-Diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

To a stirred suspension of(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry DMF (5 ml) isadded DIPEA (0.070 ml, 0.408 mmol), HATU (0.097 g, 0.255 mmol) and5,6-Diethyl-indan-2-ylamine hydrochloride (0.058 g, 0.255 mmol). Themixture is left to stir at room temperature overnight. The solvent isremoved in vacuo and purification by mass directed preparative HPLCeluting with acetonitrile: water: trifluoroacetic acid yields the titledcompound.

Alternatively, to a stirred suspension of(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Ex. 62] (0.052 g, 0.102 mmol) in dry DMF (5 ml) isadded DIPEA (0.053 ml, 0.306 mmol), HATU (0.058 g, 0.153 mmol) and5,6-Diethyl-indan-2-ylamine hydrochloride (0.035 g, 0.153 mmol). Themixture is left to stir at room temperature overnight. The solvent isremoved in vacuo and purification by mass directed preparative HPLCeluting with acetonitrile: water: trifluoroacetic acid yields the titledcompound.

Example 64(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester(0.02 g, 0.059 mmol), 5-chloro-pent-1-yne (0.0073 g, 0.071 mmol), sodiumiodide (0.009 g, catalytic amount) and potassium carbonate (0.009 g,catalytic amount) are added to acetonitrile (0.5 ml) and stirredtogether at 9 hours. Purification is carried out using mass directedpreparative HPLC eluting with acetonitrile: water: trifluoroacetic acid.Further purification is carried out by heating the resulting product inMerrifield resin in acetonitrile at 80° C. for 6 hours. The mixture isallowed to cool to room temperature and then filtered. The filtrate isconcentrated in vacuo to yield the titled product as an oil.

Example 65(R)-1-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-prop-2-ynyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

The title compound is made via an analogous procedure to(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 64) by replacing 5-chloro-pent-1-yne with2-(3-Chloro-prop-1-ynyl)-isoindole-1,3-dione, acetonitrile with DMSO andnot adding poptassium carbonate.

Examples 66 to 69

These compounds, namely(R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate, are all prepared made via an analogous procedure to(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate (Example 64) by replacing acetonitrile with DMSO and5-chloro-pent-1-yne with the appropriate alkyl halide.

Example 70(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide (i) Hydroxy-di-thiophen-2-yl-acetic acid methyl ester

Potassium hydroxide (100 ml, 1.25 M solution) is added to 2,2′-thenil(Ubichem) at room temperature and the reaction mixture is heated toreflux for 4 hours and then cooled to room temperature. The solution isacidified to pH2 and extracted with ethyl acetate (3×100 ml). Thecombined organic portions are washed with water (100 ml), dried overNa₂SO₄ and cooled to 0° C. TMS-diazomethane (20 ml of a 2M solution inhexanes) is added dropwise and the mixture is allowed to warm to roomtemperature. Acetic acid (4 ml) is added and the reaction mixture isleft at room temperature overnight. The solvent is removed in vacuo andthe crude product is dried and triturated with hexane to yield thetitled compound as a brown amorphous solid.

(ii) Hydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester

To a flask containing sodium metal (0.018 g, 0.786 mmol) under anatmosphere of argon was added a suspension comprisinghydroxy-di-thiophen-2-yl-acetic acid methyl ester [Example 70 (i)](0.2g, 0.786 mmol) and (R)-1-Aza-bicyclo[2.2.2]octan-3-ol (0.149 g, 1.179mmol) in toluene (3 ml). The reaction mixture was stirred under theinert atmosphere at 85° C. for 4 hours and the solvent was removed invacuo. The resulting crude residue was dissolved in DCM and washed withsaturated sodium bicarbonate solution. The organic portion was driedover MgSO₄ and concentrated in vacuo to yield a brown oil. Triturationwith acetonitrile affords the titled compound.

(iii)(R)-1-(3-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

Hydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.758 g, 2.17 mmol) and3(BOC-amino)propylbromide (0.775 g, 3.25 mmol) are dissolved in DMF (7ml) and heated at 60° C. for 2.5 hours. The solvent is removed in vacuoand purification of the crude residue by chromatography on C18 silica,eluting with water:acetonitrile affords the titled compound as an oil.

Examples 71 to 75

These compounds, namely(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-(2-Cyclohexylcarbamoyloxy-ethyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-1-(Benzylcarbamoyl-methyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate are all made via an analogous procedure to(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-pent-4-ynyl-1-azonia-bicyclo[2.2.2]-octanetrifluoro-acetate (Example 64) by replacing hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester withhydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)), by replacingacetonitrile with DMSO and by replacing 5-chloro-pent-1-yne with theappropriate alkyl halide.

Alternative Preparation of the Compound of Example 71 as a Bromide Salt:

A solution of 1-bromo-2-pentyne (0.51 g, 3.44 mmol) in chloroform (2 ml)is treated with polymer supported TEA resin. After a few minutes thissolution is added to a solution of hydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.0 g, 2.87mmol) in chloroform (2 ml). The resulting mixture is heated to 50° C.for 18 h and the mixture allowed to cool to room temperature. A whitesolid is isolated by filtration, washed with chloroform and dried.Recrystallisation from chloroform-acetonitrile, washing the resultantsolid with cold acetonitrile, and drying under vacuum gives(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-pent-2-ynyl-1-azonia-bicyclo[2.2.2]octanebromide.

Example 76(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

Hydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (0.03 g, 0.0857mmol), 2-chloro-N-phenyl-acetamide (0.0218 g, 0.129 mmol), sodium iodide(0.0026 g, catalytic amount) and potassium carbonate (0.0026 g,catalytic amount) are added to DMSO (1 ml) and heated to 40° C.overnight. The solvent is then removed in vacuo and purification iscarried out using mass directed preparative HPLC eluting withacetonitrile: water: trifluoroacetic acid. Further purification isrequired and is carried by chromatography on C18 silica, eluting withwater:acetonitrile to afford the titled compound.

Examples 77 to 79

These compounds, namely(R)-1-[2-(3-Cyclohexyl-ureido)-ethyl]-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(5-Fluoro-benzothiazol-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(3-phenyl-prop-2-ynyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate are all prepared by an analogous procedure to(R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoyl-methyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 76) by replacing 2-chloro-N-phenyl-acetamidewith the appropriate alkyl halide.

Example 80(R)-1-{[(Furan-2-ylmethyl)-carbamoyl]-methyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

To a solution of(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate [Example 62) (0.04 g, 0.078 mmol) in DCM (0.5 ml) isadded DIPEA (0.056 ml) and C-furan-2-yl-methylamine (0.056 ml, 0.634mmol) followed by PyBOP (0.055 g, 0.106 mmol) in DMF (1 ml). Thereaction mixture is left to stir at room temperature over 48 hours.Initial purification is carried out using Solid Phase Extraction with apH 8 pre-conditioned column (pH adjusted using Isolute CBA). Furtherpurification is carried out using mass directed preparative HPLC elutingwith acetonitrile: water: trifluoroacetic acid to afford the titledcompound.

Alterbatively, to a solution of(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate [Example 62] (0.04 g, 0.078 mmol) in DCM (0.5 ml) isadded DIPEA (0.056 ml) and C-furan-2-yl-methylamine (0.021 ml, 0.234mmol) followed by PyBroP (0.055 g, 0.118 mmol) in DMF (1 ml). Thereaction mixture is left to stir at room temperature over 48 hours.Initial purification is carried out using Solid Phase Extraction with apH 8 pre-conditioned column (pH adjusted using Isolute CBA). Furtherpurification is carried out using mass directed preparative HPLC elutingwith acetonitrile: water: trifluoroacetic acid to afford the titledcompound.

Examples 81 to 108

These compounds, namely(R)-1-[(4-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(3,4-Dichloro-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methoxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(3-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(2-Chloro-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-nitro-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(o-tolylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-1-[(4-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(phenethylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacerate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(indan-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(3-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(2-Chloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([(naphthalen-1-ylmethyl)-carbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([3-(2-oxo-pyrrolidin-1-yl)-propylcarbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(3,4-Dichloro-benzylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-thiophen-2-yl-ethylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(Cyclo-hexylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isopropylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-Ethylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(Cyclo-propylmethyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-propylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-Cyclohexylcarbamoylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{[(thiophen-2-ylmethyl)-carbamoyl]-methyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(2-methoxy-ethylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-benzylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-1-[(2-Cyano-ethylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-([2-(4-sulfamoyl-phenyl)-ethylcarbamoyl]-methyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-isopropoxy-propylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate are all prepared by an analogous procedure to(R)-1-[(furan-2-ylmethyl)-carbamoyl]-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate (Example 80)) by replacing C-furan-2-yl-methylaminewith the appropriate amine.

Example 109(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]-octanebromide (i) Fluoro-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester

To a cooled (0° C.), stirred solution of DAST (0.101 ml, 0.826 mmol) inDCM (0.5 ml) under an atmosphere of argon is added, dropwise over 10minutes, a suspension of hydroxydiphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.209 g, 0.62 mmol) in DCM (10ml). The reaction mixture is stirred at 0° C. for 1 hour after whichtime water (5 ml) is added dropwise followed by sodium hydrogencarbonate solution (3 ml, 10% w/w NaHCO₃) to adjust the pH of thesolution to pH8. The reaction mixture is diluted with DCM (10 ml) andthe organic portion is separated. The aqueous layer is extracted withDCM (10 ml) and the organic portions are combined, dried over MgSO₄ andconcentrated in vacuo. Purification of the crude residue is carried bychromatography on silica, eluting with DCM: methanol to yield the titledcompound as a brown oil.

(ii)(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]-octanebromide

To a solution of fluoro-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester [Example 109(i)] (0.034 g, 0.1mmol) in DMSO (0.25 ml) is added bromo-acetic acid phenyl ester (0.071ml, 0.5 mmol). The reaction mixture is left standing at room temperatureovernight. Purification is carried out by chromatography on C18 silica,eluting with water:acetonitrile to yield the titled compound as acolourless oil.

Examples 110 and 111

These compounds, namely(R)-3-(2-Fluoro-2,2-diphenyl-acetoxy)-1-prop-2-ynyl-1-azonia-bicyclo[2.2.2]octanebromide and(R)-1-(2-Acetoxy-ethyl)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide are prepared by an analogous method to(R)-3-(2-fluoro-2,2-diphenyl-acetoxy)-1-phenoxycarbonylmethyl-1-azonia-bicyclo[2.2.2]octanebromide (Example 109) by replacing bromo-acetic acid phenyl ester withthe appropriate alkyl halide.

Example 112(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-ureido)-ethyl]-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate

This compound is made analogously to(R)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-[2-(toluene-4-sulfonylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 49) by replacing p-toluenesulfonyl chloridewith phenyl isocyanate.

Example 113(R)-1-But-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

This compound is made analogously to(R)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-phenylcarbamoylmethyl-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 76) by replacing 2-chloro-N-phenyl-acetamidewith the appropriate alkyl halide.

Example 114(R)-1-Hex-2-ynyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate

A stirred solution comprising hydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]-oct-3-yl)ester (Example 70(ii)) (0.03 g, 0.086mmol), 1-bromo-2-hexyne (0.021 g, 0.0129 mmol), potassium carbonate(0.002 g, catalytic amount) in acetonitrile (0.5 ml) is heated to 50° C.overnight. The solvent is removed in vacuo and purification by massdirected preparative HPLC eluting with acetonitrile: water:trifluoroacetic acid yields the titled compound.

Example 115(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

To a solution of naphthalene-2-carboxylic acid (0.019 g, 0.113 mmol) inDMF (0.28 ml) is added diisopropylethylamine (0.02 ml, 0.113 mmol) inDMF (1 ml) followed by HATU (0.043 g, 0.113 mmol) in DMF (0.28 ml). Thereaction mixture is allowed to stand for 20 minutes after which time asolution comprising(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide [Example 49(ii)] (0.051 g, 0.113 mmol) anddiisopropylethylamine (0.02 ml, 0.113 mmol) in DMF (0.57 ml) is added.The reaction mixture is allowed to stand at room temperature over night.Initial purification is carried out using Solid Phase Extraction with a1 g Isolute ALB cartridge. Further purification is carried out usingmass directed preparative HPLC eluting with acetonitrile: water:trifluoroacetic acid to afford the titled compound.

Examples 116 to 157

These compounds, namely(R)-1-[2-(4-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(2,6-Dimethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-(2-[(Biphenyl-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-pyrrol-1-yl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoro-acetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methanesulfonyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-3-carbonyl)-amino]-ethyl}-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-(2-(4-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-1-[2-(3,5-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(3-Chloro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-1-[2-(4-Ethyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-trifluoromethyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-trifluoromethyl-benzoylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-trifluoro-methyl-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(3,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-methoxy-benzoyl-amino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-methoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(4-isopropoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(2,4-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(2-Cyano-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-methoxy-benzoyl-amino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propionylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(2-Cyclopentyl-acetylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyrazine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(indane-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[2-(2-Carbamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-nitro-benzoylamino)-etbyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-pyridin-3-yl-acetylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-{2-[(Furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-nitro-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1H-indazole-3-carbonyl)-amino)-ethyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(thiophene-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-{2-[(2,5-Dimethyl-2H-pyrazole-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{(2-[(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methyl-[1,2,3]thiadiazole-5-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(5-methyl-isoxazole-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(4-methoxy-thiophene-3-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-1-{2-[(3-Ethoxy-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-{2-[(5-Acetyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane(R)-1-(2-[(3-Chloro-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-{2-[(3-Bromo-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-1-{2-[(2,5-Dimethyl-furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-{2-[(5-Bromo-furan-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-(2-[(1,5-Dimethyl-1H-pyrazole-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate are all prepared by an analogous procedure to(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(naphthalene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (Example 115) by replacing naphthalene-2-carboxylicacid with the appropriate acid.

Example 158(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(methyl-phenyl-carbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane

Hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester(0.03 g, 0.09 mmol) and 2-Chloro-N-methyl-N-phenyl-acetamide (0.025 g,0.136 mmol), are dissolved in acetonitrile—DMSO (3:2, 5 ml) and stirredtogether at 18 hours at 50° C. Chloromethyl polystyrene resin(Merrifield resin) is added and the reaction stirred for an additional 4hours at room temperature. Filtration and purification using massdirected preparative HPLC eluting withacetonitrile:water:trifluoroacetic acid followed by treatment withpolymer bound Hünig's base then dissolution in ethyl acetate and washingwith water, drying and concentration in vacuo gives the titled productas a solid.

Other especially preferred compounds of formula I include compounds offormula XIV where R¹, R², R³, and R⁴ are as shown in Table 2 below, themethod of preparation being described hereinafter. All compounds arequaternary ammonium salts. The table also shows mass spectrometry data.TABLE 2 M/s Ex. R¹ and R³ R⁴ R² M+ 159

OH 485.1 160

OH 473.1 161

OH 487.2 162

OH 487.3 163

OH 480.25 164

OH 495.3 165

OH 417.2 166

OH 428.1 167

OH 433.3 168

OH 452.2 169

OH 419.9 170

OH 431.9 171

OH 405.2 172

OH 424.2 173

OH 499.3 174

OH 513.35 175

OH 513.3 176

OH 395.3 177

OH 499.3 178

OH 509.3 179

OH 501.3 180

OH 501.3 181

OH 486.2 182

OH 395.2 183

OH 499.3 184

OH 551.2 185

OH 490.3 186

OH 493.3 187

OH 580 188

OH 489 189

OH 489.6 190

OH 475.3 191

OH 464 192

OH 478 193

OH 492 194

OH 492 195

OH 464 196

OH 472 197

OH 487 198

OH 500.4 199

OH 540.6 200

OH 488 201

OH 473 202

OH 476 203

OH 472 204

OH 492 205

OH 492 206

OH 472 207

OH 491.3 208

OH — 209

OH 539.2 210

OH 589.2 211

OH 516.3 212

OH 547.2 213

OH 561.3 214

OH 571.2 215

OH 543.3 216

OH 549.3 217

OH 486.3 218

OH 549.3 219

OH 566.2 220

OH 504.3 221

OH 465.3 222

OH 605.3 223

OH — 224

OH 449.3 225

OH 598.2 226

OH 545.3 227

OH 553.3 228

OH 603.2 229

OH 525.2 230

OH 537.2 231

OH 555.3 232

OH 558.3 233

OH 447.3 234

OH 516.3 235

OH 596.3 236

OH 509.3 237

OH 555.2 238

OH 479.4 239

OH 493.35 240

OH 522 241

OH 551.2 242

OH 462.2 243

OH 474.1 244

OH 485.1 245

OH 473.2Preparation of Specific Examples

Example 159 A) Bromide salt of(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octanei) 2-Bromo-N-pyrazin-2-yl-acetamide

To a solution of 2-aminopyrazine (5.0 g, 52.6 mmol) in chloroform (250ml) under an argon atmosphere is added triethylamine (8.79 ml, 63.1mmol) and the temperature of the resulting mixture reduced to −40° C. Tothis solution is added a solution of bromoacetylbromide (4.57 ml, 52.6mmol) in chloroform dropwise over 20 minutes, and stirring continued at−20° C. to −40° C. for 1 hour. The reaction mixture is then quenched byaddition to saturated aqueous sodium bicarbonate solution. Thechloroform later is separated and washed sequentially with saturatedaqueous sodium bicarbonate solution, 0.5 M citric acid and brine.Concentration followed by purification by flash silica columnchromatography (gradient elution:ethyl acetate/hexane 4:6 to 4:1) givesthe title compound.

ii)(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide

A solution of 2-bromo-N-pyrazin-2-yl-acetamide (0.77 g, 3.56 mmol) andhydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.12 g, 3.23mmol) in dry chloroform are heated at 50° C. for 2 hours. The mixture isthen cooled to room temperature and extracted with water. The aqueouslayer is concentrated under reduced pressure then redissolved in a smallvolume of acetonitrile containing a few drops of water. The mixture isallowed to stand at room temperature for several hours, the resultingsolid is filtered and dried then redissolved in a small volume of watercontaining a few drops of acetonitrile. After several hours a solid isformed which is filtered and dried to give the title compound as a whitesolid.

B) Chloride salt of(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoyl-methyl)-1-azonia-bicyclo[2.2.2]octane

Pyrazin-2-yl-amine (400 μl, 0.5 M solution in DMF) and triethylamine(500 μl, 0.5 M solution in DMF) are combined and cooled in an ice bath.Chloroacetyl chloride (500 μl, 0.5 M solution in DMF) is added dropwiseand stirred at 0° C. for 1 hour. To the crude2-Chloro-N-pyrazin-2-yl-acetamide and hydroxy-di-thiophen-2-yl-aceticacid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (800 μl,0.25 M solution in DMF) is added triethylamine (30 μl, 1 equivalent) andthe mixture stirred at room temperature overnight.PS-Bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.3 g) and triethylamine (30μl, 1 equivalent) are added to the reaction mixture and shaken at roomtemperature for 2 hours. The reaction mixture is filtered andPS-bromoacetic acid 1.2 mmol/g (0.2 g) is added to the filtrate andshaken at 30° C. for 1 hour. The reaction mixture is passed through a 1g Isolute SPE (Al-B) cartridge. The solvent is removed in vacuo andpurification of the crude residue by mass directed preparative HPLCeluting with water:acetonitrile:trifluoroacetic acid yield the compoundas a yellow oil.

Examples 160 to 171

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanebromide,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-hydroxy-phenylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanebromide,(R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide,(R)-1-((R/S)-2-tert-Butoxycarbonyl-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide,(R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanebromide,(R)-1-(3-Cyclopropyl-prop-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide,(R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide,(R)-1-(4,4-Dimethyl-pent-2-ynyl)-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-azonia-bicyclo-[2.2.2]octanebromide,(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(4-methyl-pent-2-ynyl)-1-azonia-bicyclo[2.2.2]octanebromide, and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-pent-3-ynyl-1-azonia-bicyclo[2.2.2]octanebromide, are all prepared analogously to(R)-1-tert-Butoxy-carbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanebromide (Example 60) by replacing t-butylbromoacetate with theappropriate organic halide and heating the mixture at 50° C. for 2 to 21hours. The compounds are purified either by trituration with organicsolvents, C18 chromatography (as for Example 60) or recrystalisationfrom acetonitrile, water or chloroform. The required halides forquaternarisation are either commercially available or readilysynthesised by methods well known in the art.

Example 172(R)-1-(3-Carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octane bromide

To a stirred solution of(R)-1-(3-tert-Butoxycarbonyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide [Example 163] (0.2 g, 0.41 mmol) in methylene chloride (1.5 ml)under an argon atmosphere at room temperature is added hydrobromic acid(33% in acetic acid, 0.36 ml). After stirring at room temperatue for 30minutes, concentration is followed by dissolution in water/acetonitileand stirring for a further 30 minutes. Concentration then gives thetitle product.

Examples 173 to 175

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(3-phenylcarbamoyl-propyl)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[3-(methyl-phenylcarbamoyl)-propyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-1-(3-Benzylcarbamoyl-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicycle [2.2.2]octane trifluoroacetate are all prepared analogously to(R)-1-[(5,6-diethyl-indan-2-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate [Example 63] but by replacing(R)-1-carboxymethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Example 62] with(R)-1-(3-carboxy-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2] octane bromide [Example 172] and by replacing5,6-Diethyl-indan-2-ylamine hydrochloride with the appropriate amine.

Example 176(R)-1-(2-Amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octanechloride hydrochloride

This compound is prepared analogously to(R)-1-((R/S)-2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide [Example 49ii] but by replacing(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide [Example 49i] with(R)-1-((R/S)-2-tert-Butoxycarbonylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide [Example 164] and hydrogen bromide solution in dioxane withhydrogen chloride solution in dioxane. The product is isolated onconcentration of the reaction medium, without further purification.

Example 177(R)-1-((R/S)-2-Benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate

This compound is prepared analogously to(R)-1-(3-benzoylamino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanetrifluoroacetate [Example 2] but by replacing(R)-1-(3-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanechloride hydrochloride [Example 1(ii)] with(R)-1-((R/S)-2-amino-propyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azoniabicyclo[2.2.2]octanechloride hydrochloride.

Example 178(R)-1-[3-(tert-Butoxycarbonyl-methyl-amino)-propyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride

(3-Chloro-propyl)-methyl-carbamic acid tert-butyl ester (2.00 g 9.629mmol) is solubilised in DMF (20 ml) and polystyrene bound DIPEA added,and after a few minutes removed. This solution is then added to amixture of hydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (2.1634 g 6.419 mmol) and 200 mg of K₂CO₃ followedby the addition of sodium iodide (10 mg) and heating at 60° C. for 2days. 2.5 g Merrifield resin and 100 mg K₂CO₃ is then added to themixture and heating resumed at 40° C. for 12 hours. The resin is thenremoved, and the mixture purified by gradient C18 column chromatographyto give the title product.

Example 179(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide i)(R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

To a solution of 4-benzyloxybenzoic acid (0.126 mg, 0.55 mmol) in DMF (3ml) is added diisopropylethylamine (0.3 ml) followed by HATU (0.155 mg,0.55 mmol). The reaction mixture is stirred for 30 minutes at roomtemperature after which time a solution comprising(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide [Example 49(ii)] (0.200 g, 0.37 mmol) and theresulting mixture is stirred at room temperature over night.Purification is carried out using preparative C18 column chromatographyeluting with acetonitrile: water to afford the titled compound.

ii)(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide

To a solution of(R)-1-[2-(4-Benzyloxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide (0.075 g, 0.11 mmol) in DMF (1 ml) under an argon atmosphere isadded 10% Pd on carbon (40 mg) and the resulting solution hydrogenatedfor 3 hours. The catalyst is then removed by filtration andconcentration in vacuo yields the title compound.

Example 180(R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride i)(R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanechloride hydrochloride

To a solution of(R)-1-(2-tert-butoxycarbonylamino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanebromide [Example 49i] (8.292 g, 14.82 mmol) in dioxane (100 ml) at roomtemperature is added hydrochloric acid (18.5 ml, 4 M in dioxane). Thereaction mixture is stirred for 20 hours. The solvent is removed invacuo and purification of the crude residue by chromatography on C18silica, eluting with water:acetonitrile affords the titled product as awhite solid.

ii)(R)-1-[2-(3-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride

This is prepared analogously to(R)-1-[2-(4-Hydroxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide [Example 179] but 4-benzyloxy-benzoic acid is replaced by3-benzyloxybenzoic acid and(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanebromide hydrobromide is substituted by(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanechloride hydrochloride [Example 180 i].

Example 181(R)-1-Benzyloxycarbonylmethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide

A suspension of hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1 g, 2.96 mmol) and bromoaceticacid benzyl ester (0.516 ml, 3.26 mmol) in ethylacetate (20 ml) isheated at 50° C. for 2 hours. The reaction mixture is cooled to roomtemperature and the precipitate removed by filtration. Recrystallisationfrom acetonitrile (20 ml) gives the title compound.

Example 182(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-methylamino-ethyl)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide

(2-Bromo-ethyl)-methyl-carbamic acid tert-butyl ester (0.09 g, 0.38mmol) is added to a solution of hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (0.265 g, 0.79 mmol) in DMF (10ml). The resulting mixture is heated at 60° C. for 5 hours andconcentrated. This procedure is repeated twice giving the title compoundas a mixture containing unreacted hydroxy-diphenyl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester.

Example 183(R)-1-[2-(Benzoyl-methyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

The crude product from Example 182 is dissolved in acetonitrile (10 ml)and filtered then cooled over an ice bath, under an argon atmosphere. Tothis cooled solution is added triethylamine (127 μl) followed by benzoylbromide (64 μl) and the reaction stirred for 1 hour. Purification iscarried out using mass directed preparative HPLC eluting withacetonitrile:water:trifluoroacetic acid to afford the titled compound.

Example 184(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (i) N-(2-Bromo-phenyl)-2-chloro-acetamide

2-Bromoaniline (371 μl, 467 mmol) and triethylamine (651 μl, 5.84 mmol)are dissolved in DMF (2 ml) and cooled in an ice bath. Chloroacetylchloride (371 μl, 4.67 mmol) is added dropwise and stirred at 0° C. for1 hour. The solvent is removed in vacuo and used crude in the next step.

ii)(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

N-(2-Bromo-phenyl)-2-chloro-acetamide (155 mg, 0.622 mmol) andhydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester(210 mg, 0.622 mmol) are dissolved in DMF (4 ml). The reaction mixtureis stirred at 0° C. for 2 hours. PS-Bromoacetamidomethyl-NovaGel 2.3mmol/g (0.5 g) is added to the reaction mixture and shaken at roomtemperature for 4 hours. PS-Triphenylphosphine 3 mmol/g (0.5 g) is addedto the reaction mixture and shaken at room temperature overnight. Thereaction mixture is then passed through a 1 g Isolute SPE (Al-B)cartridge. The solvent is removed in vacuo and purification of the cruderesidue by mass directed preparative HPLC eluting withwater:acetonitrile:trifluoroacetic acid yields the titled compound.

Example 185 to 189

These compounds, namely(R)-1-[(3,4-Dimethyl-isoxazol-5-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-methyl-[1,2,4]thiadiazol-5-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(5-Bromo-3,4-dimethyl-pyridin-2-yl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-1-[(2,S-Dimethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate, and(R)-1-[(2-Ethyl-2H-pyrazol-3-ylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanetrifluoroacetate are all prepared analogously to(R)-1-[(2-Bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Example 184] by replacing 2-Bromoaniline with theappropriate amine.

Example 190(R)-1-{2-[(Furan-2-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate

To a stirred solution of 2-furoic acid (91.5 mg, 8.21 mmol) and HATU(284 mg, 7.52 mmol) in DMF (7.5 ml) is added polymer bound morpholine,2.5 mmol/g (1.36 g, 34.2 mmol). The reaction mixture is left to stand atroom temperature for 15 minutes after which time, a solution comprisingof(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanechloride hydrochloride [Example 180 i]] (310 mg, 6.84 mmol) in DMF (7.5ml) is added. The reaction mixture is stirred at room temperatureovernight. The reaction mixture is passed through a 2 g Isolute SPE(Al-B) cartridge. The filtrate is concentrated in vacuo and purificationof the crude residue by chromatography on C18 silica, eluting withwater:acetonitrile affords the title compound as a white solid.

Example 191(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate (i)(R)-1-{2-[1-tert-Butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate

This compound is prepared analogously to(R)-1-{2-[(Furan-2-carbonyl)-amino]ethyl}-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate [Example 190] by replacing 2-furoic acid with1-BOC-azetidine-3-carboxylic acid.

(ii)(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate

(R)-1-2-[(1-tert-butoxycarbonyl-azetidine-3-carbonyl)-amino]ethyl-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate is dissolved in TFA: DCM (1:1) (2 ml) and stirred atroom temperature for 1 hour. TFA:DCM (2 ml) is added to the reactionmixture to complete the reaction. The solvent is removed in vacuo andpurification of the crude residue by mass directed preparative HPLCeluting with water:acetonitrile:trifluoroacetic acid yields the titledcompound.

Example 192 to 195

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-pyrrolidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-piperidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((S)-piperidine-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate and(R)-1-{2-[((S)-Azetidine-2-carbonyl)-amino)-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate are prepared analogously to(R)-1-{2-[(Azetidine-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Example 191] by replacing 1-BOC-azetidine-3-carboxylicacid with the corresponding BOC protected amino acid.

Example 196(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridine-2-ylcarbamoylmethyl)-azonia-bicyclo[2.2.2]octane trifluoroacetate

This compound is prepared analogously to(R)-1-[(2-Bromo-phenylcarbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate [Example 184]. However instead of usingPS-triphenylphosphine, BEMP 2.3 mmol/g (0.1 g, 1 eqv) is used with thePS-bromoacetamidomethyl-NovaGel 2.3 mmol/g (0.3 g, 1 eqv).

Example 197(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-pyrimidin-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanechloride

This compound is prepared analogously to(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanechloride [Example 159B] by substituting hydroxy-di-thiophen-2-yl-aceticacid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and Pyrazin-2-yl-amine withhydroxy-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester and4-Methyl-pyrimidin-2-ylamine.

Examples 198 to 201

These compounds, namely(R)-1-[(6-Ethyl-pyridin-2-ylcarbamoyl)methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-trifluoromethyl-pyridin-4-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octane trifluoroacetate,R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(3-hydroxy-pyridin-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanetrifluoroacetate, and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrimidin-2-ylcarbamoylmethyl)-1-azoniabicyclo[2.2.2]octane trifluoroacetate are all prepared analogously to(R)-1-[(2-bromo-phenyl-carbamoyl)-methyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)]-1-azonia-bicyclo[2.2.2]octanechloride [Example 184] by substituting 2-bromoaniline with thecorresponding heterocyclic amines, however in these examplesPS-triphenylphosphine is not used.

Examples 202 to 206

The title compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-oxazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanechloride,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanechloride,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(5-methyl-thiazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanechloride,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[(4-methyl-thiazol-2-ylcarbamoyl)-methyl]-1-azonia-bicyclo[2.2.2]octanechloride, and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyridin-3-ylcarbamoylmethyl)-1-azoniabicyclo[2.2.2]octane chloride, are all prepared analogously to(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanechloride [Example 159B] by substituting hydroxy-di-thiophen-2-yl-aceticacid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester withhydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)esterand replacing Pyrazin-2-yl-amine with the corresponding heterocyclicamines.

Example 207(R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-[2-[thiophene-2-carbonyl)-amino]-ethyl]-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate

To a stirred solution of 2-thiophenecarboxylic acid (15.4 mg, 0.12 mmol)and HATU (42 mg, 0.11 mmol) in DMF (0.6 ml) is added triethylamine (42μl, 0.3 mmol). The reaction mixture is left to stand for 20 minutesafter which time, a solution comprising of(R)-1-(2-amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetyl)-1-azonia-bicyclo[2.2.2]octanebromide [Example 49 ii)] (45 mg, 0.1 mmol) in DMF (0.6 ml) is added. Thereaction mixture is stirred at room temperature overnight. The reactionmixture is passed through a 1 g Isolute SPE (Al-B) cartridge and thefiltrate concentrated in vacuo. Purification by mass directedpreparative HPLC eluting with water:acetonitrile:trifluoracetic acidyields the titled compound.

Examples 208 to 241

These compounds, namely(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.21octane hexafluoro phosphate,(R)-1-{2-[(3-Chloro-4-methyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluoro phosphate,(R)-1-{2-[(5-Chloro-3-methyl-benzo-[b]thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-hydroxy-6-methyl-pyridine-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexafluoro-phosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(thieno[3,2-b]thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluoro-phosphate,(R)-1-{2-[(6-Fluoro-4H-benzo[1,3]dioxine-8-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluoro phosphate,(R)-1-(2-[(5-Bromo-thiophene-2-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(2-propoxy-benzoylamino)-ethyl]-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-1-[2-(5-Chloro-2-methoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(pyridine-4-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-1-[2-(2,6-Dimethoxy-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-1-(2-[(5-Bromo-pyridine-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-1-(2-[(3,5-Dimethyl-isoxazole-4-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluoro phosphate,(R)-1-{2-[(1-Hydroxy-cyclo-propanecarbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]-octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(2-trifluoro-methyl-[1,8]naphthyridine-3-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexa-fluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(6-methyl-pyridine-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octanehexafluorophosphate,(R)-1-[2-(Cyclopropanecarbonyl-amino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octanehexafluorophosphate,(R)-1-[2-(4-Chloro-3-sulfamoyl-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(4,5,6,7-tetrahydro-benzo[c]thiophene-1-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]-octanehexafluorophosphate,(R)-1-[2-[(2,7-Dimethyl-imidazo[1,2-a]pyridine-3-carbonyl)-amino]-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexa-fluorophosphate,(R)-1-{2-[(3-Chloro-4-methanesulfonyl-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane hexafluorophosphate,(R)-1-{2-[(5-Chloro-thiophene-2-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-1-[2-(3-Chloro-4-fluoro-benzoylamino)-ethyl]-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(3-methyl-benzo[b]thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexa-fluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-[(3-methyl-5-trifluoromethyl-isoxazole-4-carbonyl)-amino]-ethyl]-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(1-oxo-but-2-ynylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octanehexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-2-[(2-methoxy-pyridine-3-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octanehexafluoro-phosphate,(R)-1-(2-[(5-Dimethylsulfamoyl-2-methyl-furan-3-carbonyl)-amino]-ethyl}-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane hexafluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-[2-(3-phenyl-propynoylamino)-ethyl]-1-azonia-bicyclo-[2.2.2]octanehexafluorophosphate,(R)-1-[2-[(5-Chloro-4-methoxy-thiophene-3-carbonyl)-amino]-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octanehexa-fluorophosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[((R)-tetrahydro-furan-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octane hexafluoro-phosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(tetrahydro-pyran-4-carbonyl)-amino]-ethyl)-1-azonia-bicyclo[2.2.2]octanehexafluoro phosphate,(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(2-[(3-methoxy-thiophene-2-carbonyl)-amino]-ethyl)-1-azonia-bicyclo-[2.2.2]octanehexafluoro-phosphate, and(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-{2-[(5-methoxy-thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexafluoro-phosphate, are all prepared analogously to(R)-3-(2-Hydroxy-2,2-diphenyl-acetyl)-1-{2-[thiophene-2-carbonyl)-amino]-ethyl}-1-azonia-bicyclo[2.2.2]octanehexafluorophosphate [Ex. 207] by substituting 2-thiophenecarboxylic acidwith the corresponding carboxylic acid.

Example 242(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide i) 2-Bromo-N-isoxazol-3-yl-acetamide

To a stirred solution of bromoacetylbromide (5.36 ml, 61.6 mmol) indiethylether (100 ml) at −40° C. is added, dropwise over 20 minutes, asolution of 3-aminoisoxazol (5.0 ml, 67.0 mmol) and triethylamine (8.5ml, 61.4 mmol) in diethylether (20 ml). Additional diethylether (50 ml)is added and stirring continued for 3 hours. The reaction mixture isfiltered and the solution then washed with 1 M sodium carbonatesolution, 1 M hydrochloric acid and brine. Concentration followed bypurification by flash silica column chromatography (ethylacetate/iso-hexane 4:7) gives the title compound as a white solid.

ii)(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide

A solution of 2-Bromo-N-isoxazol-3-yl-acetamide (0.82 g, 4.0 mmol) inchloroform/acetonitrile(1:1) is added to a solution ofhydroxyl-diphenyl-acetic acid(R)-(1-aza-bicyclo-[2.2.2]oct-3-yl)ester(1.12 g, 3.32 mmol) in dry chloroform (10 ml) and the resulting mixtureheated to 55° C. under an argon atmosphere for 4 hours. The mixture isthen cooled to room temperature and concentrated. The residue isdissolved in acetonitrile and concentration followed by redissolution inhot acetone and cooling gives a jelly like precipitate which isfiltered. Recrystallisation of the crude precipitate from acetonitrilecontaining a few drops of water followed by further crystallisation fromacetonitrile gives the title compound as light brown crystals.

In an alterntaive method for preparing2-Bromo-N-isoxazol-3-yl-acetamide, to a stirred solution ofbromoacetylbromide (5.36 ml, 61.6 mmol) in diethylether (100 ml) at −40°C. is added, dropwise over 20 minutes, a solution of 3-aminoisoxazol(5.0 ml, 67.7 mmol) and triethylamine (8.5 ml, 61.4 mmol) indiethylether (20 ml). Additional diethylether (50 ml) is added andstirring continued for 3 hours. The reaction mixture is filtered and thesolution then washed with 1 M sodium carbonate solution, 1 Mhydrochloric acid and brine. Concentration followed by purification byflash silica column chromatography (ethyl acetate/iso-hexane 3:7) givesthe title compound as a white solid.

Example 243(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide

A solution of 2-Bromo-N-isoxazol-3-yl-acetamide [Example 242 i]) (0.70g, 3.5 mmol) in chloroform (10 ml) is added to a solution ofhydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (1.01 g, 2.9 mmol) acetonitrile(5 ml) and the resulting mixture heated to 55° C. under an argonatmosphere for 4 hours. The mixture is then cooled to room temperatureand concentrated. The residue is triturated with ethylacetate and thenpurification by C-18 reverse phase column chromatography (eluent:water-acetonitrile) to give the title compound as a white foam.

Example 244(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide i) 2-Bromo-N-pyrimidin-4-yl-acetamide

To a solution of 4-aminopyrimidine (7.0 g, 73.6 mmol) in chloroform (300ml) under an argon atmosphere is added triethylamine (12.3 ml, 88.3mmol) and the temperature of the resulting mixture reduced to −40° C. Tothis solution is added a solution of bromoacetylbromide (6.4 ml, 73.6mmol) in chloroform (5 ml) dropwise and stirring continued for 1.5hours. The reaction mixture is then quenched by addition to saturatedaqueous sodium bicarbonate solution. The chloroform later is separatedand washed with 0.5 M citric acid solution. Concentration followed bypurification by flash silica column chromatography (gradientelution:ethyl acetate/hexane 1:4 to methanol/ethyl acetate 1:10) givesthe title compound.

ii)(R)-3-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-(pyrimidin-4-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octanebromide

A solution of 2-Bromo-N-pyrimidin-4-yl-acetamide (0.90 g, 4.17 mmol) andhydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.32 g, 3.79mmol) in dry chloroform-acetonitrile (20 ml+4 ml) are heated at 50° C.for 3 hours. The mixture is then cooled to room temperature andconcentrated. Purification by reverse phase C18 column chromatography(gradient elution 100% water to 100% acetonitrile) gives afterconcentration a light brown solid. The solid was triturated with hotacetonitrile then dissolved in hot acetonitrile containing a few dropsof water. After standing at 5° C. for several hours crystals are formedwhich are filtered and dried to give the title compound.

Example 245(R)-3-(2-Hydroxy-2,2-diphenyl-acetoxy)-1-(pyrazin-2-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane

A solution of 2-bromo-N-pyrazin-2-yl-acetamide (1.50 g, 6.94 mmol) andhydroxyl-diphenyl-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester(2.13 g, 6.31 mmol) in dry chloroform (10 ml) are heated at 50° C. for 2hours. The mixture is then cooled to room temperature filtered andconcentrated. The resulting foam is dissolved in acetonitrile and cooledto −20° C., an orange oil is formed from which the acetonitrile layer isdecanted. The orange oil is dissolved in water and washed withchloroform before concentration. Redissolution in hot water followed byprecipitation by cooling to room temperature gives the title product asa white solid.

Further especially preferred compounds of formula I include compounds offormula XIV where R¹, R², R³, and R⁴ are as shown in Table 3 below, themethod of preparation being described hereinafter. All compounds arequaternary ammonium salts. The table also shows mass spectrometry data.TABLE 3 M/s Ex. R¹ and R³ R⁴ R² M+ 246

OH 448.3 247

OH 408.3Preparation of Specific Examples

Example 2461-Allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo-[2.2.2]octane

A solution of bromo-acetic acid allyl ester (0.8 g, 4.46 mmol) andhydroxy-di-thiophen-2-yl-acetic acid(R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 70(ii)) (1.3 g, 3.7mmol) in dry chloroform are heated at 50° C. for 2 hours. The contentsare then allowed to cool and then concentrated in vacuo. This residue isthen taken up in 1% water in acetone at reflux and allowed to cool toroom temp. After several hours a solid is formed which is filtered anddried to give the title compound as a brown solid.

Example 2471-Carboxymethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane

To a stirred solution of1-allyloxycarbonylmethyl-3-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-1-azonia-bicyclo[2.2.2]octane(Example 246) (0.79 g, 1.50 mmol) in dry chloroform, under argon, isadded tetrakis-palladium triphenyl phosphine (0.02 g, 0.017 mmol). Themixture is strirred at room temp., under argon, for 20 minutes beforemorpholine (0.196 ml, 2.25 mmol) is added. Stirring is continued for afurther 4 hrs at room temp. The mixture is concentrated in vacuo andpurified by gradient C18 column chromatography to give a pale yellowsolid. The solid is then redissolved in a small volume of acetonitrilecontaining a few drops of water. After several hours a solid is formedwhich is filtered and dried to give the title compound as a pale yellowsolid.

1. A compound of formula I

in salt or zwitterionic form wherein R¹ and R³ are each independently aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—; R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyloptionally substituted by hydroxy; R⁴ is C₁-C₈-alkyl substituted by—NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹,—O—CO—NHR¹², —O—CO—R¹³ or —CO—O—R¹⁴, or R⁴ is C₃-C₁₀-alkynyl optionallysubstituted by a C₃-C₁₅-carbocyclic group or a 4- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁵ is hydrogen or C₁-C₈-alkyl; R⁶ isC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in each caseoptionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is a C₃-C₁₅-carbocyclicgroup; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ is hydrogen, C₁-C₈-alkyloptionally substituted by cyano, amino, nitro, carboxy, C₁-C₈-alkoxy, aC₃-C₁₅-carbocyclic group, or by a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R¹¹ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkyl-C₁-C₈-alkoxy or C₁-C₈-alkyl-O—R¹⁵; R¹² is aC₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkyl or a C₃-C₁₅-carbocyclicgroup; R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group, C₁-C₈-alkenyl, orC₁-C₈-alkyl optionally substituted by a C₃-C₁₅-carbocyclic group; andR¹⁵ is a C₃-C₁₅-carbocyclic group.
 2. A compound according to claim 1,wherein R¹ and R³ are each independently a C₃-C₁₅-carbocyclic group or a4- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur; R² is halo or hydroxy; R⁴ isC₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R², —O—CO—R¹³ or —CO—O—R⁴, or R⁴ isC₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclic group or a4- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur; R⁵ is hydrogen orC₁-C₈-alkyl; R⁶ is C₁-C₈-alkyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in eachcase optionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is a C₃-C₁₅-carbocyclicgroup; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ is C₁-C₈-alkyl optionallysubstituted by cyano, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group or by a4- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R¹² is a C₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkyl; and R¹⁴is hydrogen, a C₃-C₁₅-carbocyclic group, C₁-C₈-alkenyl, or C₁-C₈-alkyloptionally substituted by a C₃-C₁₅-carbocyclic group.
 3. A compoundaccording to claim 2, wherein R¹ and R³ are each independently aC₆-C₁₀-carbocyclic aromatic group or a 4- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur; R² is halo or hydroxy; R⁴ is C₁-C₈-alkyl substituted by—NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R²,—O—CO—R¹³ or —CO—O—R⁴, or R⁴ is C₃-C₈-alkynyl optionally substituted bya C₃-C₁₀-carbocyclic group or a 4- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁵ is hydrogen or C₁-C₄-alkyl; R⁶ is C₁-C₄-alkyl, C₂-C₈-alkynylor C₁-C₄-alkoxy in each case optionally substituted by aC₃-C₁₀-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R⁶ is a C₃-C₁₀-carbocyclic group or a 4- to 10-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁷ is a C₃-C₁₀-carbocyclic group; R⁸ is aC₃-C₁₀-carbocyclic group; R⁹ is hydrogen or C₁-C₄-alkyl; R¹⁰ isC₁-C₄-alkyl optionally substituted by cyano, C₁-C₄-alkoxy, aC₃-C₁₀-carbocyclic group or by a 4- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R¹⁰ is a C₃-C₁₀-carbocyclic group or a 4- to 10-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R¹² is a C₃-C₁₀-carbocyclic group; R¹³ isC₁-C₄-alkyl; and R¹⁴ is hydrogen, a C₃-C₁₀-carbocyclic group,C₁-C₄-alkenyl, or C₁-C₄-alkyl optionally substituted by aC₃-C₁₀-carbocyclic group.
 4. A compound of formula I

in salt or zwitterionic form wherein R¹ and R³ are each independently aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—; R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyloptionally substituted by hydroxy; R⁴ is C₁-C₈-alkyl substituted by—NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹,—O—CO—NHR¹², —O—CO—R¹³ or —CO—O—R⁴, or R⁴ is C₃-C₁₀-alkynyl optionallysubstituted by a C₃-C₁₅-carbocyclic group or a 4- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁵ is hydrogen or C₁-C₈-alkyl; R⁶ isC₁-C₈-alkyl, C₂-C₈-alkenyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in each caseoptionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is a C₃-C₁₅-carbocyclicgroup; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ is hydrogen, C₁-C₈-alkyloptionally substituted by cyano, amino, nitro, carboxy, C₁-C₈-alkoxy, aC₃-C₁₅-carbocyclic group, or by a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R¹⁰ is a C₃-C₁₅-carbocyclic group or a 4- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R¹¹ is hydrogen, C₁-C₈-alkyl,C₁-C₈-alkyl-C₁-C₈-alkoxy or C₁-C₈-alkyl-O—R¹⁵; R¹² is aC₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkyl or a C₃-C₁₅-carbocyclicgroup; R¹⁴ is hydrogen, a C₃-C₁₅-carbocyclic group, or C₁-C₈-alkyloptionally substituted by a C₃-C₁₅-carbocyclic group; and R¹⁵ is aC₃-C₁₅-carbocyclic group.
 5. A compound according to claim 4, wherein R¹and R³ are each independently a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur; R² is halo or hydroxy; R⁴ isC₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷,—NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R², —O—CO—R¹³ or —CO—O—R⁴, or R⁴ isC₃-C₁₀-alkynyl optionally substituted by a C₃-C₁₅-carbocyclic group or a4- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur; R⁵ is hydrogen orC₁-C₈-alkyl; R⁶ is C₁-C₈-alkyl, C₂-C₁₀-alkynyl or C₁-C₈-alkoxy in eachcase optionally substituted by a C₃-C₁₅-carbocyclic group or a 4- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is a C₃-C₁₅-carbocyclicgroup; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ is C₁-C₈-alkyl optionallysubstituted by cyano, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group or by a4- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₅-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R¹² is a C₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkyl; and R¹⁴is hydrogen, a C₃-C₁₅-carbocyclic group or C₁-C₈-alkyl optionallysubstituted by a C₃-C₁₅-carbocyclic group.
 6. A compound according toclaim 5, wherein R¹ and R³ are each independently a C₆-C₁₀-carbocyclicaromatic group or a 4- to 12-membered heterocyclic group having at leastone ring heteroatom selected from nitrogen, oxygen and sulphur; R² ishalo or hydroxy; R⁴ is C₁-C₈-alkyl substituted by —NHR⁵, —NR⁵—CO—R⁶,—NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—N H—R¹², —O—CO—R¹³ or—CO—O—R¹⁴, or R⁴ is C₃-C₈-alkynyl optionally substituted by aC₃-C₁₀-carbocyclic group or a 4- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁵ is hydrogen or C₁-C₄-alkyl; R⁶ is C₁-C₄-alkyl, C₂-C₈-alkynylor C₁-C₄-alkoxy in each case optionally substituted by aC₃-C₁₀-carbocyclic group or a 4- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R⁶ is a C₃-C₁₀-carbocyclic group or a 4- to 10-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁷ is a C₃-C₁₀-carbocyclic group; R⁸ is aC₃-C₁₀-carbocyclic group; R⁹ is hydrogen or C₁-C₄-alkyl; R¹⁰ isC₁-C₄-alkyl optionally substituted by cyano, C₁-C₄-alkoxy, aC₃-C₁₀-carbocyclic group or by a 4- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R¹⁰ is a C₃-C₁₀-carbocyclic group or a 4- to 10-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R¹² is a C₃-C₁₀-carbocyclic group; R¹³ isC₁-C₄-alkyl; and R¹⁴ is hydrogen, a C₃-C₁₀-carbocyclic group orC₁-C₄-alkyl optionally substituted by a C₃-C₁₀-carbocyclic group.
 7. Acompound of formula I

in salt or zwitterionic form wherein R¹ and R³ are each independently aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or —CR¹R²R³ together form a group of formula

where R is a bond, —O—, —S—, —CH₂—, —CH═CH—, —CH₂—CH₂—, amino or—N(CH₃)—; R² is hydrogen, halo, hydroxy, C₁-C₈-alkoxy or C₁-C₈-alkyloptionally substituted by hydroxy; R⁴ is C₁-C₈-alkyl substituted by—NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —OR¹¹,—O—CO—NHR², —O—CO—R¹³ or —CO—O—R¹⁴, or R⁴ is C₃-C₁₀-alkynyl optionallysubstituted by a C₃-C₁₅-carbocyclic group or a 5- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁵ is hydrogen or C₁-C₈-alkyl; R⁶ isC₁-C₈-alkyl or C₁-C₈-alkoxy in either case optionally substituted by aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur, or R⁶ is a C₃-C₁₅-carbocyclic group or a 5- to 12-memberedheterocyclic group having at least one ring heteroatom selected fromnitrogen, oxygen and sulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is aC₃-C₁₅-carbocyclic group; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ ishydrogen, C₁-C₈-alkyl optionally substituted by cyano, amino, nitro,carboxy, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group, or by a 5- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R¹¹ is hydrogen, C₁-C₈-alkyl, C₁-C₈-alkyl-C₁-C₈-alkoxy orC₁-C₈-alkyl-O—R¹⁵; R¹² is a C₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkylor a C₃-C₁₅-carbocyclic group; R¹⁴ is hydrogen, C₁-C₈-alkyl or aC₃-C₁₅-carbocyclic group; and R¹⁵ is a C₃-C₁₅-carbocyclic group.
 8. Acompound according to claim 7, wherein R¹ and R³ are each independentlya C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R² is halo or hydroxy; R⁴ is C₁-C₈-alkyl substituted by —NHR⁵,—NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R²,—O—CO—R¹³ or —CO—O—R¹⁴, or R⁴ is C₃-C₁₀-alkynyl optionally substitutedby a C₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁵ is hydrogen; R⁶ is C₁-C₈-alkyl or C₁-C₈-alkoxy in eithercase optionally substituted by a C₃-C₁₅-carbocyclic group or a 5- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁶ is aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₅-carbocyclic group; R⁸ is a C₃-C₁₅-carbocyclicgroup; R⁹ is hydrogen or C₁-C₈-alkyl; R¹⁰ is C₁-C₈-alkyl optionallysubstituted by cyano, C₁-C₈-alkoxy, a C₃-C₁₅-carbocyclic group or by a5- to 12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₅-carbocyclic group or a 5- to 12-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R¹² is a C₃-C₁₅-carbocyclic group; R¹³ is C₁-C₈-alkyl; and R¹⁴is hydrogen, C₁-C₈-alkyl or a C₃-C₁₅-carbocyclic group.
 9. A compoundaccording to claim 8, wherein R¹ and R³ are each independently aC₆-C₁₀-carbocyclic aromatic group or a 5- to 12-membered heterocyclicgroup having at least one ring heteroatom selected from nitrogen, oxygenand sulphur; R² is halo or hydroxy; R⁴ is C₁-C₈-alkyl substituted by—NHR⁵, —NR⁵—CO—R⁶, —NR⁵—CO—NH—R⁷, —NR⁵—SO₂—R⁸, —CO—NR⁹R¹⁰, —O—CO—NH—R²,—O—CO—R¹³ or —CO—O—R⁴, or R⁴ is C₃-C₈-alkynyl optionally substituted bya C₃-C₁₀-carbocyclic group or a 5- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁵ is hydrogen; R⁶ is C₁-C₄-alkyl or C₁-C₄-alkoxy in eithercase optionally substituted by a C₃-C₁₀-carbocyclic group or a 5- to12-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R⁵ is aC₃-C₁₀-carbocyclic group or a 5- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R⁷ is a C₃-C₁₀-carbocyclic group; R⁸ is a C₃-C₁₀-carbocyclicgroup; R⁹ is hydrogen or C₁-C₄-alkyl; R¹⁰ is C₁-C₄-alkyl optionallysubstituted by cyano, C₁-C₄-alkoxy, a C₃-C₁₀-carbocyclic group or by a5- to 10-membered heterocyclic group having at least one ring heteroatomselected from nitrogen, oxygen and sulphur, or R¹⁰ is aC₃-C₁₀-carbocyclic group or a 5- to 10-membered heterocyclic grouphaving at least one ring heteroatom selected from nitrogen, oxygen andsulphur; R¹² is a C₃-C₁₀-carbocyclic group; R¹³ is C₁-C₄-alkyl; and R¹⁴is hydrogen, C₁-C₄-alkyl or a C₃-C₁₀-carbocyclic group.
 10. A compoundaccording to claim 1, which is also a compound of formula XIV

where R¹, R², R³, and R⁴ are as shown in the following table: R¹ and R³R⁴ R²

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

F

F

F

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH


11. A compound according to claim 1, which is also a compound of formulaXIV

where R¹, R², R³, and R⁴ are as shown in the following table: R¹ and R³R⁴ R²

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH

OH


12. A compound according to claim 1, which is also a compound of formulaXIV

where R¹, R², R³, and R⁴ are as shown in the following table: R¹ and R³R⁴ R²

OH

OH


13. A compound according to claim 1 in combination with another drugsubstance which is an anti-inflammatory, a bronchodilator, anantihistamine, a decongestant or an anti-tussive drug substance. 14.(canceled)
 15. A pharmaceutical composition comprising as activeingredient a compound according to claim 1 in combination with anotherdrug substance which is an anti-inflammatory, a bronchodilator, anantihistamine, a decongestant or an anti-tussive drug substance,optionally together with a pharmaceutically acceptable diluent orcarrier. 16-17. (canceled)
 18. A process for the preparation of acompound of formula I as claimed in claim 1 which comprises (i) (A)reacting a compound of compound of formula II

or a protected form thereof where R¹, R² and R³ are as defined in claim1, with a compound of formula IIIR⁴—X  III where R⁴ is as hereinbefore defined and X is chloro, bromo oriodo; (B) for the preparation of compounds of formula I where R⁴ isC₁-C₈-alkyl substituted by —NR⁵—CO—R⁶ where R⁵ and R⁶ are as defined inclaim 1, reacting a compound of formula IV

or a protected form thereof where R¹, R², R³ and R⁵ are as defined inclaim 1, optionally in the presence of a coupling agent, and T denotesC₁-C₈-alkylene, with a compound of formula V

where R⁶ is as defined in claim 1 or an amide-forming derivative thereofsuch as an acid halide; (C) for the preparation of compounds of formulaI where R⁴ is C₁-C₈-alkyl substituted by —NR⁵—CO—NH—R⁷ where R⁵ and R⁷are as defined in claim 1, reacting a compound of formula IV or aprotected form thereof where R¹, R², R³ and R⁵ are as defined in claim 1and T denotes C₁-C₈-alkylene, with a compound of formula VIO═C═N—R⁷  VI where R⁷ is as defined in claim 1; (D) for the preparationof compounds of formula I where R⁴ is C₁-C₈-alkyl substituted by—NR⁵—SO₂—R⁸ where R⁵ and R⁸ are as defined in claim 1, reacting acompound of formula IV or a protected form thereof where R¹, R², and R³are as defined in claim 1 and T denotes C₁-C₈-alkylene, with a compoundof formula VII

where R⁸ is as defined in claim 1 and X is halo; or (E) for thepreparation of compounds of formula I where R⁴ is C₁-C₈-alkylsubstituted by —CO—NR⁹R¹⁰ where R⁹ and R¹⁰ are as defined in claim 1,reacting a compound of formula VIII

or a protected form thereof where R¹, R², and R³ are as defined in claim1 and T denotes C₁-C₈-alkylene, optionally in the presence of a couplingagent, or an amide-forming derivative thereof such as an acid halide,with a compound of formula IX

where R⁹ and R¹⁰ are as defined in claim 1; and (ii) recovering theproduct in salt or zwitterionic form.
 19. A pharmaceutical compositioncomprising as active ingredient a compound according to claim
 1. 20. Amethod of treating a condition mediated by the muscarinic M3 receptor ina subject in need of such treatment, which comprises administering tosaid subject an effective amount of a compound of formula I as definedin claim 1 in free form or in the form of a pharmaceutically acceptablesalt.
 21. A method of treating an inflammatory or obstructive airwaysdisease in a subject in need of such treatment, which comprisesadministering to said subject an effective amount of a compound offormula I as defined in claim 1 in free form or in the form of apharmaceutically acceptable salt.